- Open Access
Therapeutic potential of ADAM10 modulation in Alzheimer’s disease: a review of the current evidence
Cell Communication and Signaling volume 21, Article number: 60 (2023)
Alzheimer’s disease (AD), the most common neurodegenerative disease worldwide, is caused by loss of neurons and synapses in central nervous system. Several causes for neuronal death in AD have been introduced, the most important of which are extracellular amyloid β (Aβ) accumulation and aggregated tau proteins. Increasing evidence suggest that targeting the process of Aβ production to reduce its deposition can serve as a therapeutic option for AD management. In this regard, therapeutic interventions shown that a disintegrin and metalloproteinase domain-containing protein (ADAM) 10, involved in non-amyloidogenic pathway of amyloid precursor protein processing, is known to be a suitable candidate. Therefore, this review aims to examine the molecular properties of ADAM10, its role in AD, and introduce it as a therapeutic target to reduce the progression of the disease.
Alzheimer’s disease (AD) is known as the most common chronic neurodegenerative disease. As the disease progresses, it disrupts the patient's memory and cognitive functions . AD is characterized by aggregation of amyloid β (Aβ)-containing extracellular plaques and tau-containing intracellular neurofibrillary tangles in the neurons [2, 3]. However, AD initially presents with transient forgetness, but as the disease progresses, other symptoms such as impaired speech and vision and long-term memory dysfunction . Although the rate of progression can vary, the average life expectancy after diagnosis is three to nine years .
AD is a multifactorial disease, which means environmental factors also play an essential role in addition to genetic factors. However, only up to 2% of AD cases are inherited, known to start early and progress faster . In sporadic AD, genes encoding amyloid precursor protein (APP), PSEN1, and PSEN2 are known to be critical factors, which are involved in over-production of Aβ [7, 8], which is a significant component of Aβ plaques. Two other mutations in the ABCA7 and SORL1 genes have recently been observed in patients with the familial AD .
Most AD cases are not inherited and experience the onset of symptoms at an older age, typically 65 years. More than 600 genes have been studied as AD susceptibility agents. The most potent genetic risk factor for disseminated AD is APOEε4 , one of the four alleles of Apolipoprotein E. Between 40 and 80% of people with AD have at least one APOEε4 allele . The APOEε4 allele triples the disease risk in heterozygotes and 15-fold in homozygotes. Some studies have also shown that alleles in the TREM2 gene are 3–5 times more likely to develop AD .
It is not yet clear how the production and accumulation of Aβ cause pathogenesis. The amyloid hypothesis refers to the accumulation of Aβ peptides as the main event that causes neuronal destruction. Accumulation of Aβ fibrils, believed to be responsible for impaired cell ion homeostasis, leading to induce neuronal apoptosis. It is also known that Aβ is selectively present in mitochondria in brain cells. It is made with AD and also inhibits the functions of certain enzymes and the use of glucose by neurons [13, 14].
Despite many efforts to understand the pathophysiology of AD, no definitive cure has been identified yet. Increasing evidence suggest that designing treatment regimens to target the factors involved in the pathophysiology of the disease can be constructive. One of the best treatment candidates for AD appears to be the Aβ production pathway, where a variety of enzymes and intracellular factors are involved. In this regard, numerous studies introduce that inducing the non-amyloidogenic APP processing pathway and inhibition of amyloidogenic APP processing can be an effective therapy in AD. A disintegrin and metalloproteinase domain-containing protein (ADAM) 10 is one of the most important proteases involved in APP processing, which is shown its activation leads to reduce Aβ production and exhibits a protective role agains AD. Therefore, this review focuses on the role of ADAM10 in pathophysiology of AD, and introduces it as a probable therapeutic target to reduce disease progression.
ADAM10 structure and synthesis
ADAM is a family of metalloproteinases consist of approximately 750 amino acids with proteolytic activity to process ectodomain of diverse cell-surface receptors . One of the most important members of this family is ADAM10 which is mostly known due to its role in the processing of the amyloid precursor protein (APP) . However, ADAM10 is expressed in different cells, the most important of which are vascular cells, leukocytes neurons, and tumor cells . ADAM10 is synthesized co-translationally via the rough endoplasmic reticulum, maturated and transported by the Golgi apparatus . Removal of the ADAM10 pro-domain is the main change during its maturation which keeps ADAM10 in an inactive state through a cysteine switch mechanism in a way that coordinates the zinc ion in the catalytic site and prevents ADAM10 proteolytic activity . Pro-protein convertase is involved in ADAM10 maturation through its cleavage in several sites such as PC7 in Golgi apparatus . The pro-domain is required as an intramolecular chaperon for folding correction, and it seems not to has a mere inhibitory function in ADAM10 . This process has been proved followed by finding a large proportion of ADAM10 in the Golgi apparatus in breast carcinoma cells by confocal microscopy . In addition to pro-domain removal, N-glycosylation of ADAM10 at four positions occurs during its transport to the membrane . The other main domains of ADAM10 structure include disintegrin and an inactive zymogen containing C-terminal . Although disintegrin domain seems not to be necessary for ADAM10 protease activity , the short intracellular C-terminus appears to play a crucial role as it has been demonstrated that the cleavage of epidermal growth factor is impaired in ADAM10−/− cells with overexpressed cytoplasmic domain deletion mutant of the proteinase . Additionally, several binding sites have been noted for cytoplasmic domain of ADAM10 which seems to be involved in regulatory events, including two proline-rich putative Src homology 3 (SH3) binding domains  and a binding site for calmodulin . The SH3 binding domains direct ADAM10 are involved in direct ADAM10 to the postsynaptic membrane in neurons, while juxtamembrane binding site is involved in ADAM10 basolateral localization in epithelial cells . In addition to bio-synthesis of ADAM10, its translocation to the membrane is a process which has been considered in different studies to modulate its physiologic function. There are a series of intracellular factors involved in translocation of ADAM10 in different steps of its maturation. In this regard, synapse-associated protein-97 (SAP97) is known as one of the main factors which governs ADAM10 transport from the Golgi outposts to the synapse, without any effects on ADAM10 trafficking from the endoplasmic reticulum. Mechanistically, protein kinase C (PKC) has been shown to mediate phosphorylation of SAP97 SRC homology 3 domain which regulates SAP97 association with ADAM10 and its translocation from Golgi to synapse . Due to the sufficiency of SAP97 in ADAM10 exit from the endoplasmic reticulum, further studies conducted to introduce several other factors involved in this process. In this case, a subgroup of tetraspanins consist of eight cysteines in the large extracellular domain (Tspan10, Tspan5, Tspan15, Tspan14, Tspan17 and Tspan33) were known to be involved in ADAM10 exit from the endoplasmic reticulum . In addition, it has been reported that an arginine-rich (723RRR) sequence is responsible for ADAM10 retention in the endoplasmic reticulum and its inefficient surface trafficking .
The mature form of ADAM10 has a molecular weight of ∼ 65 kDa . ADAM10 ectodomain shedding leads to leave a membrane-anchored C-terminal fragment with a ∼ 10 kDa of weight and release of a ∼ 55 kDa soluble ADAM10. This process shows that regardless of the protease activity of ADAM10, this factor itself is affected by other proteases the most important of which are ADAM9 and 15 and γ-secretase . One of the main components of γ-secretase, presenilin, affects ADAM10 leading to release its intracellular domain. This released domain is translocated to nucleus which thought to play a part in gene regulation .
ADAM10 as a biomarker in Alzheimer’s disease
ADAM10 has previously been present in human CSF in several forms: an immature form that retains protamine, an unprocessed form, and a large cut solution form . However, studies in AD patients have shown that the expression of ADAM10 in their platelets is associated with changes. Initially, there were reports of a decrease in ADAM10, but further studies reveal no significant link between ADAM10 levels and cognitive symptoms in AD patients, so it has been proposed that these changes might be due to the medications taken by patients . Manzini et al. in a study examined ADAM10 levels in AD patients compared with healthy individuals who have reported increased levels of its substrates in patients' platelets (17).
This evidence suggests that ADAM10 might be used as a biomarker for AD diagnosis, although further research is needed to corroborate this theory. Table 1 summarizes the studies indicating ADAM10 alterations in samples from AD patients.
Roles of ADAM10 in Alzheimer’s disease
ADAM10 and Aβ in Alzheimer’s disease
The most known activity of ADAM10, as a main α-secretase enzyme [31, 32], is its role in processing the APP. APP, a type I transmembrane glycoprotein, is expressed in different mammal cells, especially neurons. APP is known because it serves as Aβ precursor, including 12–15 residues of the membrane-spanning and 28 amino acids of the extracellular region of APP . Although the underlying cause of AD remains unknown, Aβ accumulation as plaques is known to be a hallmark of the disease because of its association with the other processes involved in AD pathophysiology, such as oxidative stress and neuroinflammation . Due to this issue, in recent years, therapeutic interventions to slow the progression of AD have been focused on reducing Aβ production. In the processing of APP, there are two pathways which addressing them can help understand the role of ADAM10 in AD pathophysiology. In Amyloidogenesis pathway, cleavage of transmembrane residue of APP by β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), the main β-secretase enzyme, contributes to release β-stubs. In addition, cleavage of APP by BACE-1 leads to liberate soluble N-terminus of APP and a membrane bound C-terminal fragment (C99). At the second step, C99 fragment is cleaved by γ-secretase which contributes to Aβ release into the extracellular space . The other pathway of APP processing, known as non-Amyloidogenesis pathway, is initiated by α-secretase activity. The effect of α-secretase on APP contributes to generate and release soluble APP-α (sAPPα), other APP ectodomain variant known as a neuroprotective and neurotrophic factor [35, 36]. Additionally, several roles have been noted for sAPPα, including modulation of basal synaptic transmission likely via γ-aminobutyric acid type B (GABAB) receptor subunit 1a . However, explaining these two pathways can theoretically help to present therapeutic goals, although in practice more studies are required to prove this claim. In this regard, it has been proven that suppression of Amyloidogenesis pathway through suppression of BACE-1 and γ-secretase exhibits protective effects in different models of AD . Similarly, inducing the non-Amyloidogenesis pathway via increasing the expression or activity of α-secretase leads to reduce Aβ production and accumulation . As described, ADAM10 is one of the main α-secretases, and it has been presented as a suitable therapeutic target to modulate Aβ production.
ADAM10 and TREM2 in Alzheimer’s disease
Triggering receptor expressed on myeloid cells-2 (TREM2) is a receptor located on cell surface and consists of a V-immunoglobulin extra-cellular domain and cytoplasmic tail . TREM2 is mainly expressed in myeloid cells including granulocytes, dendritic cells, tissue-specific macrophages like osteoclasts, alveolar macrophages and Kuppfer cells . In CNS, TREM2 is expressed in microglia cells and plays a great part in regulation of their activity . Physiologically, TREM 2 is involved in regulation of phagocytosis, cell proliferation, and inflammation via its effect on downstream targets including the PI3K/AKT and ERK1/2 signaling pathways . However, increased expression of TREM2 has been detected in different pathologies, such as Parkinson’s disease, traumatic brain injury, and AD  indicating its probable role in pathophysiology of these diseases. In AD, the most important role noted for TREM2 is its interactions with Aβ plaques and regulation of neuroinflammation, in a way that TREM2 is involved in microglia recruitment to Aβ plaques [42, 43]. Activation of mentioned intracellular pathways followed by TREM2-Aβ axis contributes to enhance Aβ clearance and induce inflammatory responses . In addition, there is a soluble form of TREM2 (sTREM2) which is generated followed by the effect of α-secretase on extracellular domain of TREM2 . The sTREM2 is known as a neuroprotective factor due to its role in enhancement of Aβ plaque degradation . However, it seems that the most important α-secretase involved in TREM2 shedding and generation of sTREM2 is ADAM10. In this regard, it can be referred to a study indicating ADAM10 role in TREM2 shedding . In this study it was shown that TREM2 shedding at the H157-S158 bond and generation of sTREM2 inhibited by metalloprotease inhibitors, G1254023X and siRNA targeting ADAM10, but not matrix metalloproteinases 2/9, and ADAM17 siRNA. This process can be expressed as a therapeutic target to increase sTREM2 levels through ADAM10 activation, and further studies in this regard can be constructive.
ADAM10 and microRNAs in Alzheimer’s disease
microRNAs (miRs) are a group of non-coding RNA molecules involved in regulation of the expression of proteins through binding to 3’UTR of their mRNA . In addition to their physiologic roles, it is clearly understood that aberrant expression of miRs plays a great part in different pathologies, such as cancers and neurologic disorders . In recent years, numerous studies indicate that miRs are involved in AD pathophysiology, as their up- or down-regulation has been detected in these patients. In addition, pre-clinical studies demonstrate that miRs regulate different processes in AD, the most important of which are Aβ production (reviewed at ). In this regard, miRs have been shown to regulate the activity of α-secretase, β-secretase, and γ-secretase. In a computational study, it was reported that miR-103, miR-1306, and miR-107, which their aberrant expression has been detected in AD patients, may affect the expression of ADAM10 to regulate APP processing . miR-221, a downregulated miR in AD, has been shown to reduce the expression of ADAM10 in SH-SY5Y cells . In another study, it has been indicated that miR-144 and miR-451 regulate the expression of ADAM10 in HeLa and human neuroblastoma SH-SY5Y cells .
Collectively, these studies clarify the essential role of miRs to regulate ADAM10 expression and activity. However, more studies are required to present other miRs involved in this process and introduce them as therapeutic options in AD.
Regulation of ADAM10 expression and activity by intracellular pathways in Alzheimer’s disease
The expression of ADAM10 is regulated at different stages of transcription (i.e. retinoic acid, sirtuins, SOX-2, and PAX-2), translation, and post-translation levels (reviewed at ). However, there are several intracellular pathways with altered activity in AD which their relationship with ADAM10 has been less analyzed. Extracellular signal‑regulated protein kinase (ERK)1/2 is one of the main intracellular pathways involved in regulation of different aspects of cell life, including cell proliferation and protein synthesis . However, this pathway has been shown to be disrupted in patients with AD and play a role in regulation of Aβ production, tau phosphorylation, and neuroinflammation . Regarding the effect of ERK1/2 on ADAM10, it has been demonstrated that ERK1/2 induces ADAM10 expression through induction of cAMP-response element binding protein (CREB) activity leading to enhance APP processing and sAPPα production . Additionally, S100A7, a novel AD biomarker, has been shown to promote non-Amyloidogenesis pathway through induction of ADAM10 by mediating of ERK1/2 .
Phosphatidylinositol 3 kinase (PI3K)/AKT signaling pathway is the other main intracellular pathway with altered activity in AD . In this regard, it has been indicated that activation of estrogen receptors contributes to promote non-Amyloidogenic processing of APP through activation of the PI3K/AKT pathway leading to enhance ADAM10 activity .
Although the role of these two pathways in the regulation of ADAM10 activity is inevitable, the exact mechanism of this regulation in AD is still unknown. However, in non-AD models it has been noted that PI3K/AKT and ERK1/2 signaling pathways regulate several factors involved in regulation of ADAM10 expression, such as Y sex determination region (SRY)-box 2 (SOX-2) [59, 60]. However, more studies are required to determine the exact mechanism of the involvement of the PI3K/AKT and ERK1/2 pathways in regulation of ADAM10 expression and investigate them as a therapeutic target in AD (Figs. 1, 2).
ADAM10 and synaptic plasticity in Alzheimer’s disease
Different experiences, whether they be stressful event, learning in a classroom, or using of a psychoactive substance, influence the brain through modifying the activity of specific neural circuitry. Synaptic plasticity is an experience-dependent change in neuronal connection strength that provides the basis for most learning and memory models . This type of cellular learning consists of specific stimulation protocols generating a long-term synapse strengthening, known as long-term potentiation (LTP), or a weakening of the said long-term synapses, known as long-term depression (LTD). Although AD is known to be associated with loss of neurons in different regions of the brain, the hypothesis indicating the alteration in the molecular mechanisms of synaptic plasticity underlying this imbalance is widely accepted . However, the association between various molecular aspects of AD and synaptic plasticity has been investigated in different studies.
During AD progression, the efficiency of synapses is decreased followed by a significant decrement in synaptic vesicles. In this regard, progressive changes in gene expression in CA1 region of MCI and AD brains occurs in a way that a significant decrement in different steps of synaptic function-related proteins has been detected in these patients . In a closer inspection, reduced expression of synaptophysin and synaptogyrin (presynaptic vesicle trafficking proteins) syntaxin 1and synaptotagmin (vesicle coupling/fusion/release proteins), and PSD-95 (postsynaptic function regulators) has been detected in CA1 of subjects with MCI and AD . In the case of Aβ, it has been observed that Aβ oligomers alter molecular pathways involved in LTP which initiate LTP decline and LTD increase in hippocampus slices . Impaired learning and memory followed by Aβ injection into the brain of mice may prove the effect of Aβ on synapse plasticity . These results may provide an insight into the role of ADAM10 in synaptic plasticity via modulation of Aβ production, in a way that reduced ADAM10 activity in AD brains can alter synaptic plasticity by mediating of Aβ accumulation. On the other hand, the interaction between synaptic plasticity-related processes and ADAM10 activity has been shown in several studies. In this regard, it has been reported that LTD differentially regulates the synaptic availability and activity of ADAM10 via promoting its endocytosis . Additionally, in this study it was shown that synapse-associated protein 97 (SAP97) is required for LTD-induced ADAM10 trafficking. In addition to SAP97, LTP has been shown to trigger ADAM10 association to clathrin adaptor AP2, as shown to be increased in AD brains, leading to induce its endocytosis [66, 67]. Interestingly, it has been reported that Aβ oligomers-induced aberrant plasticity process can reduce Aβ generation via modulation of ADAM10 synaptic availability . These results have led to introduce ADAM10 endocytosis as a suitable target for therapy in AD. In this case, it has been elucidated that treatment of APP/PS1 mice with a cell-permeable peptide (PEP3), which interferes with ADAM10 endocytosis, contributes to upregulate the postsynaptic localization and activity of ADAM10 and eventually, promote synaptic plasticity and improve cognitive deficit . However, there is a long way to use these agents in clinical trials because of their non-specific activity and probable side effects. In this regard, using of agents which modulate several intracellular pathways may be considered to modulate the endocytosis of ADAM10. For instance, the PI3K/AKT signaling pathway has been shown to inhibit clathrin-mediated endocytosis via modulation of AP2 activity [70, 71]. On the other hand, it has been reported that inhibition of the PI3K/AKT signaling pathway by Aβ plaques contributes to downregulate synaptic related proteins, such as synaptophysin and post-synaptic density-95, which eventually may influence ADAM10 synaptic availability . Also, it has been shown that activation of the PI3K/AKT pathway promotes dendrite branch density and increase synaptic protein expression leading to increased levels of ADAM10 in AD mice . In a mechanistic inspection, it can be said that changes to synaptic plasticity may influence intracellular pathways, mainly the PI3K/AKT pathway , which is known as a regulator for ADAM10 expression and endocytosis. This process may be mediated by GSK-3, as it has been demonstrated that LTP-induced PI3K/AKT/GSK-3 regulates LTD in CA1 pyramidal neurons negatively [75, 76]. Therefore, it can be concluded that activation of LTP inhibits LTD along with activation of the PI3K/AKT pathway leading to induce clathrin-mediated endocytosis of ADAM10. On the other hand, caspase-3, which plays a crucial role in the pathophysiology of AD , has been shown to be activated by Aβ oligomers, which in turn cleaves AKT, activates LTD , and possibly inhibits endocytosis of ADAM10 (Fig. 3). Regardless the role of synaptic plasticity in regulation of ADAM10 availability, it has been elucidated that function of ADAM10 regulates the synaptic plasticity, mainly via cleavage of several factors such as APP, neuroligin 1, and N-cadherin .
Pharmacologic modulation of ADAM10 in Alzheimer’s disease
According to the important role of ADAM10 in the processing of APP, it is clearly understood that inducing its expression or activity in AD exhibits neuroprotective effects. Numerous studies investigate the effect of different drugs and natural compounds on AD by mediating of ADAM10.
FDA-approved drugs for Alzheimer’s disease
Although AD is known as one of the main challenges for health systems worldwide, just two classes of drugs are approved for using in AD patients, namely N-methyl d-aspartate (NMDA) antagonists and cholinesterase enzyme inhibitors (naturally derived, synthetic hybrid analogues). Cholinesterase enzyme inhibitors are used in AD based on the cholinergic hypothesis which proposes the reduction of acetylcholine (ACh) biosynthesis in AD. NMDA receptor antagonists, the other group of FDA-approved drugs for AD, are used due to overactivation of NMDA receptors in the brains of AD patients which results in an elevation in Ca2+ influx to the neurons and subsequently induction of oxidative stress and neuronal apoptosis [80, 81]. However, the neuroprotective effects of mentioned drugs on other pathologic changes in AD has been shown in several studies. In this regard, it has been reported that memantine, a NMDA receptor antagonist, induces the expression and activity of ADAM10 and reduces Aβ oligomers formation in 3xTg-AD mice leading to improve cognitive function . Additionally, it has been observed that rivastigmine, a cholinesterase enzyme inhibitor, up-regulates the ADAM10 levels leading to increase sAPPα generation in 3 × Tg mice . Regarding the other cholinesterase enzyme inhibitor, donepezil, it has been elucidated that treatment of SH-SY5Y cells by donepezil increases sAPPα formation via induction of ADAM10 activity .
Melatonin is an endogenous hormone responsible for regulation of circadian rhythm, free radicals, and neuroprotection . In addition, melatonin is also prescribed in patients with sleep disorders . However, the association between melatonin and ADAM10 activity is very interesting. It is clearly understood that melatonin is an inducer for ADAM10 transcription through direct effects on the promoter regions 2304 and 1193, subsequently, increase ADAM10 expression [87, 88]. Decreased levels of melatonin in AD patients has been introduced as a mechanism for decreased ADAM10 expression and Aβ accumulation in these patients [89, 90]. However, the mechanism of melatonin-induced ADAM10 expression has been well-studied. In this regard, it has been shown that melatonin induces ERK1/2 phosphorylation via binding to melatonin receptor, and increases ADAM10 expression leading to up-regulate non-Amyloidogenic pathway of APP processing . Also, melatonin has been indicated to induce ADAM10 expression and suppress BACE1 expression through activation of melatonin G protein-coupled receptors in human neuronal SH-SY5Y cells . It has been demonstrated that melatonin increases ADAM10 expression in the hippocampus of aged mice through upregulation of sirtuin1, one of the main regulators of ADAM10 transcription .
Statins are a group of lipid-lowering agents. They suppress conversion of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) to through inhibition of HMG-CoA reductase . In addition to effectiveness of statins in regulation of lipid levels, they are known due to their pleiotropic effects, including immunomodulatory, anti-oxidant, and anti-tumor properties . Also, statins exert neuroprotective effects in different neurologic pathologies, such as neurodegenerative diseases . In AD, these drugs affect different pathologic processes, especially Amyloidogenesis and APP processing . In this regard, it has been shown that statins increase APP processing leading to generate sAPPα in N2a mouse neuroblastoma cells through an isoprenoid-mediated mechanism, and possibly ADAM10 induction . In addition, it has been demonstrated that atorvastatin increases α-secretase activity and stimulates sAPPα production in N2a cells through an ERK-independent mechanism .
In recent years, numerous studies focused on the protective effects of different natural compounds on AD. Although these agents are best known because of their anti-inflammatory and antioxidant properties, they can have far-reaching effects on other aspects of AD pathophysiology. One of the most important effects of natural compounds on AD is their role in modulating Aβ production, which is mediated by their effect on the expression of factors involved in its production, such as BACE1, γ-secretase, and α-secretase. However, the association between different natural compounds and ADAM10 expression and activity in models of AD summarized in Table 2.
It is clearly understood that ADAM10 has a protective effect against AD progression due to its role in processing of APP in non-amyloidogenic pathway. Pharmacologic evidence also suggests its potential as a therapeutic target in AD. In addition, alterations in ADAM10 expression and activity in different samples from AD patients can be encouraging to introduce it as a therapeutic option in AD. However, there are different natural compounds, with low side effects, which can be used in clinical trials due to their effects on ADAM10.
Availability of data and materials
Clark TA, et al. Oxidative stress and its implications for future treatments and management of Alzheimer disease. Int J Biomed Sci IJBS. 2010;6(3):225.
Knopman DS, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7(1):33–33.
Breijyeh Z, Karaman R. Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules. 2020;25:24.
Bird TD. Alzheimer disease overview. GeneReviews®[Internet]. 2018.
Todd S, et al. Survival in dementia and predictors of mortality: a review. Int J Geriatr Psychiatry. 2013;28(11):1109–24.
Jellinger K. The neuropathological diagnosis of Alzheimer disease. Ageing Dementia. 1998; 97–118.
Kim JH. Genetics of Alzheimer’s disease. Dementia Neurocogn Disord. 2018;17(4):131–6.
Borchelt DR, et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996;17(5):1005–13.
Hall K, et al. Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba. Neurology. 2006;66(2):223–7.
Gureje O, et al. APOE epsilon4 is not associated with Alzheimer’s disease in elderly Nigerians. Ann Neurol. 2006;59(1):182–5.
Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci. 2006;103(15):5644–51.
Carmona S, et al. The role of TREM2 in Alzheimer’s disease and other neurodegenerative disorders. Lancet Neurol. 2018;17:721–30.
Carbonell F, et al. Spatially distributed amyloid-β reduces glucose metabolism in mild cognitive impairment. J Alzheimers Dis. 2020;73:543–57.
Rhein V, Eckert A. Effects of Alzheimer’s amyloid-beta and tau protein on mitochondrial function—role of glucose metabolism and insulin signalling. Arch Physiol Biochem. 2007;113(3):131–41.
Huovila A-PJ, et al. Shedding light on ADAM metalloproteinases. Trends Biochem Sci. 2005;30(7):413–22.
Lammich S, et al. Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci. 1999;96(7):3922–7.
Moss ML, et al. ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein. J Biol Chem. 2011;286(47):40443–51.
Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci. 1990;87(14):5578–82.
Anders A, et al. Regulation of the α-secretase ADAM10 by its prodomain and proprotein convertases. FASEB J. 2001;15(10):1837–9.
Gutwein P, et al. ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles. FASEB J. 2003;17(2):292–4.
Fahrenholz F, et al. α-Secretase activity of the disintegrin metalloprotease ADAM 10: influences of domain structure. Ann N Y Acad Sci. 2000;920(1):215–22.
Horiuchi K, et al. Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx. Mol Biol Cell. 2007;18(1):176–88.
Marcello E, et al. Synapse-associated protein-97 mediates α-secretase ADAM10 trafficking and promotes its activity. J Neurosci. 2007;27(7):1682–91.
Wild-Bode C, et al. A basolateral sorting signal directs ADAM10 to adherens junctions and is required for its function in cell migration. J Biol Chem. 2006;281(33):23824–9.
Saraceno C, et al. SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation. Cell Death Dis. 2014;5(11):e1547–e1547.
Saint-Pol J, et al. Regulation of the trafficking and the function of the metalloprotease ADAM10 by tetraspanins. Biochem Soc Trans. 2017;45(4):937–44.
Marcello E, et al. An arginine stretch limits ADAM10 exit from the endoplasmic reticulum. J Biol Chem. 2010;285(14):10376–84.
Tousseyn T, et al. ADAM10, the rate-limiting protease of regulated intramembrane proteolysis of Notch and other proteins, is processed by ADAMS-9, ADAMS-15, and the γ-secretase. J Biol Chem. 2009;284(17):11738–47.
Sogorb-Esteve A, et al. Levels of ADAM10 are reduced in Alzheimer’s disease CSF. J Neuroinflammation. 2018;15(1):213–213.
Mukaetova-Ladinska EB, et al. Plasma and platelet clusterin ratio is altered in Alzheimer’s disease patients with distinct neuropsychiatric symptoms: findings from a pilot study. Int J Geriatr Psychiatry. 2015;30(4):368–75.
Jorissen E, et al. The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J Neurosci. 2010;30(14):4833–44.
Kuhn PH, et al. ADAM10 is the physiologically relevant, constitutive α-secretase of the amyloid precursor protein in primary neurons. EMBO J. 2010;29(17):3020–32.
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.
Rajasekhar K, Chakrabarti M, Govindaraju T. Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer’s disease. Chem Commun. 2015;51(70):13434–50.
Khezri MR, et al. The role of ERK1/2 pathway in the pathophysiology of Alzheimer’s disease: an overview and update on new developments. Cell Mol Neurobiol. 2022;1–15.
Morishima-Kawashima M, Ihara Y. Alzheimer’s disease: β-Amyloid protein and tau. J Neurosci Res. 2002;70(3):392–401.
Hampel H, et al. β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification. Alzheimer’s Res Ther. 2020;12(1):1–14.
Khezri MR, et al. Metformin in Alzheimer’s disease: an overview of potential mechanisms, preclinical and clinical findings. Biochem Pharmacol. 2022;114945.
Postina R, et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest. 2004;113(10):1456–64.
Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000;164(10):4991–5.
Gratuze M, Leyns CE, Holtzman DM. New insights into the role of TREM2 in Alzheimer’s disease. Mol Neurodegener. 2018;13(1):1–16.
Sessa G, et al. Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur J Neurosci. 2004;20(10):2617–28.
Yeh FL, Hansen DV, Sheng M. TREM2, microglia, and neurodegenerative diseases. Trends Mol Med. 2017;23(6):512–33.
Kleinberger G, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014;6(243):243ra86.
Zhong L, et al. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model. Nat Commun. 2019;10(1):1–16.
Thornton P, et al. TREM 2 shedding by cleavage at the H157–S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant. EMBO Mol Med. 2017;9(10):1366–78.
Lu TX, Rothenberg ME. MicroRNA. J Allergy Clin Immunol. 2018;141(4):1202–7.
Acunzo M, et al. MicroRNA and cancer—a brief overview. Adv Biol Regul. 2015;57:1–9.
Khezri MR, et al. MicroRNAs in the pathophysiology of Alzheimer’s disease and Parkinson's disease: an overview. Mol Neurobiol. 2022; 1–15.
Augustin R, et al. Computational identification and experimental validation of microRNAs binding to the Alzheimer-related gene ADAM10. BMC Med Genet. 2012;13(1):1–12.
Manzine PR, et al. microRNA 221 targets ADAM10 mRNA and is downregulated in Alzheimer’s disease. J Alzheimers Dis. 2018;61(1):113–23.
Cheng C, et al. MicroRNA-144 is regulated by activator protein-1 (AP-1) and decreases expression of Alzheimer disease-related a disintegrin and metalloprotease 10 (ADAM10). J Biol Chem. 2013;288(19):13748–61.
Endres K, Deller T. Regulation of alpha-secretase ADAM10 in vitro and in vivo: genetic, epigenetic, and protein-based mechanisms. Front Mol Neurosci. 2017;10:56.
Chetram MA, Hinton CV. PTEN regulation of ERK1/2 signaling in cancer. J Recept Signal Transduct. 2012;32(4):190–5.
Guo C, et al. Intranasal lactoferrin enhances α-secretase-dependent amyloid precursor protein processing via the ERK1/2-CREB and HIF-1α pathways in an Alzheimer’s disease mouse model. Neuropsychopharmacology. 2017;42(13):2504–15.
Qin W, et al. S100A7, a novel Alzheimer’s disease biomarker with non-amyloidogenic α-secretase activity acts via selective promotion of ADAM-10. PLoS ONE. 2009;4(1):e4183.
Gabbouj S, et al. Altered insulin signaling in Alzheimer’s disease brain–special emphasis on PI3K-Akt pathway. Front Neurosci. 2019;13:629.
Zhang S-Q, et al. Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation. PLoS ONE. 2013;8(8):e71913.
Peltier J, et al. Akt increases sox2 expression in adult hippocampal neural progenitor cells, but increased sox2 does not promote proliferation. Stem Cells Dev. 2011;20(7):1153–61.
Stavridis MP, et al. A discrete period of FGF-induced Erk1/2 signalling is required for vertebrate neural specification. 2007.
Citri A, Malenka RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology. 2008;33(1):18–41.
Torres DMC, Cardenas FP. Synaptic plasticity in Alzheimer’s disease and healthy aging. Rev Neurosci. 2020;31(3):245–68.
Counts SE, et al. Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology. 2014;79:172–9.
Knobloch M, et al. Aβ oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms. J Neurosci. 2007;27(29):7648–53.
Karthick C, et al. Time-dependent effect of oligomeric amyloid-β (1–42)-induced hippocampal neurodegeneration in rat model of Alzheimer’s disease. Neurol Res. 2019;41(2):139–50.
Musardo S, et al. ADAM10 in synaptic physiology and pathology. Neurodegener Dis. 2014;13(2–3):72–4.
Marcello E, et al. Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease. J Clin Investig. 2013;123(6):2523–38.
Marcello E, et al. Amyloid-β oligomers regulate ADAM10 synaptic localization through aberrant plasticity phenomena. Mol Neurobiol. 2019;56(10):7136–43.
Musardo S., et al. The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer’s disease. Mol Ther. 2022.
Zheng J, et al. Clathrin-dependent endocytosis is required for TrkB-dependent Akt-mediated neuronal protection and dendritic growth. J Biol Chem. 2008;283(19):13280–8.
Pascolutti R, et al. Molecularly distinct clathrin-coated pits differentially impact EGFR fate and signaling. Cell Rep. 2019;27(10):3049-3061.e6.
Zeng Y, et al. Tripchlorolide improves cognitive deficits by reducing amyloid β and upregulating synapse-related proteins in a transgenic model of Alzheimer’s Disease. J Neurochem. 2015;133(1):38–52.
Yan L, et al. 7, 8-Dihydroxycoumarin alleviates synaptic loss by activated PI3K-Akt-CREB-BDNF signaling in Alzheimer’s disease model mice. J Agri Food Chem. 2022.
Marsden W. Synaptic plasticity in depression: molecular, cellular and functional correlates. Prog Neuropsychopharmacol Biol Psychiatry. 2013;43:168–84.
Peineau S, et al. A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases. Mol Brain. 2009;2:22.
Peineau S, et al. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron. 2007;53(5):703–17.
Khezri MR, Ghasemnejad-Berenji M. The role of caspases in Alzheimer’s disease: pathophysiology implications and pharmacologic modulation. J Alzheimer's Dis. 1–20.
Jo J, et al. Aβ(1–42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β. Nat Neurosci. 2011;14(5):545–7.
Yuan X-Z, et al. The role of ADAM10 in Alzheimer’s disease. J Alzheimers Dis. 2017;58:303–22.
Eldufani J, Blaise G. The role of acetylcholinesterase inhibitors such as neostigmine and rivastigmine on chronic pain and cognitive function in aging: a review of recent clinical applications. Alzheimer’s Dementia Transl Res Clin Interv. 2019;5:175–83.
Sharma K. Cholinesterase inhibitors as Alzheimer’s therapeutics. Mol Med Rep. 2019;20(2):1479–87.
Martinez-Coria H, et al. Memantine improves cognition and reduces Alzheimer’s-like neuropathology in transgenic mice. Am J Pathol. 2010;176(2):870–80.
Ray B, et al. Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease. Transl Psychiatry. 2020;10(1):47.
Zimmermann M, et al. Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines. J Neurochem. 2004;90(6):1489–99.
Hardeland R, Pandi-Perumal S, Cardinali DP. Melatonin. Int J Biochem Cell Biol. 2006;38(3):313–6.
Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336(3):186–95.
Shukla M, et al. Melatonin stimulates the nonamyloidogenic processing of β APP through the positive transcriptional regulation of ADAM10 and ADAM17. J Pineal Res. 2015;58(2):151–65.
Shukla M, et al. Mechanisms of melatonin in alleviating Alzheimer’s disease. Curr Neuropharmacol. 2017;15(7):1010–31.
Waldhauser F, Steger H. Changes in melatonin secretion with age and pubescence. J Neural Transm Suppl. 1986;21:183–97.
Zhou JN, et al. Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res. 2003;35(2):125–30.
Panmanee J, et al. Melatonin regulates the transcription of βAPP-cleaving secretases mediated through melatonin receptors in human neuroblastoma SH-SY5Y cells. J Pineal Res. 2015;59(3):308–20.
Mukda S, et al. Melatonin administration reverses the alteration of amyloid precursor protein-cleaving secretases expression in aged mouse hippocampus. Neurosci Lett. 2016;621:39–46.
Demierre M-F, et al. Statins and cancer prevention. Nat Rev Cancer. 2005;5(12):930–42.
Hindler K, et al. The role of statins in cancer therapy. Oncologist. 2006;11(3):306–15.
Wang Q, et al. Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol. 2011;230(1):27–34.
Petanceska SS, et al. Statin therapy for Alzheimer’s disease. J Mol Neurosci. 2002;19(1):155–61.
Pedrini S, et al. Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLoS Med. 2005;2(1):e18.
Parvathy S, et al. Atorvastatin-induced activation of Alzheimer’s α secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding. J Neurochem. 2004;90(4):1005–10.
Pereira Vatanabe I, et al. ADAM10 plasma and CSF levels are increased in mild Alzheimer’s disease. Int J Mol Sci. 2021;22(5):2416.
OliveiraMonteiro MPA, et al. ADAM10 plasma levels predict worsening in cognition of older adults: a 3-year follow-up study. Alzheimer’s Res Ther. 2021;13(1):18.
Colciaghi F, et al. Platelet APP, ADAM 10 and BACE alterations in the early stages of Alzheimer disease. Neurology. 2004;62(3):498.
Manzine PR, et al. ADAM10 as a biomarker for Alzheimer’s disease: a study with Brazilian elderly. Dement Geriatr Cogn Disord. 2013;35(1–2):58–66.
Di Maio A, et al. Analysis of mRNA and protein levels of CAP2, DLG1 and ADAM10 genes in post-mortem brain of schizophrenia, Parkinson’s and Alzheimer’s disease patients. Int J Mol Sci. 2022;23(3):1539.
Bekris LM, et al. ADAM10 expression and promoter haplotype in Alzheimer’s disease. Neurobiol Aging. 2012;33(9):2229.e1-2229.e9.
Huang W-H, et al. Influence of ADAM10 polymorphisms on plasma level of soluble receptor for advanced glycation end products and the association with Alzheimer’s disease risk. Front Genet. 2018;9:540.
Kim M, et al. Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate α-secretase activity. Hum Mol Genet. 2009;18(20):3987–96.
Narasingapa RB, et al. Activation of α-secretase by curcumin-aminoacid conjugates. Biochem Biophys Res Commun. 2012;424(4):691–6.
Li W-X, et al. Icariin, a major constituent of flavonoids from Epimedium brevicornum, protects against cognitive deficits induced by chronic brain hypoperfusion via its anti-amyloidogenic effect in rats. Pharmacol Biochem Behav. 2015;138:40–8.
Fanaee-Danesh E, et al. Astaxanthin exerts protective effects similar to bexarotene in Alzheimer’s disease by modulating amyloid-beta and cholesterol homeostasis in blood-brain barrier endothelial cells. BBA Mol Basis Dis. 2019;1865(9):2224–45.
Obregon DF, et al. ADAM10 activation is required for green tea (–)-epigallocatechin-3-gallate-induced α-secretase cleavage of amyloid precursor protein. J Biol Chem. 2006;281(24):16419–27.
Fernandez JW, et al. EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP. FEBS Lett. 2010;584(19):4259–67.
Sathya M, et al. Resveratrol intervenes cholesterol-and isoprenoid-mediated amyloidogenic processing of AβPP in familial Alzheimer’s disease. J Alzheimers Dis. 2017;60(s1):S3–23.
Shi C, et al. Bilobalide regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. Neurochem Int. 2011;59(1):59–64.
Elfiky AM, et al. Quercetin stimulates the non-amyloidogenic pathway via activation of ADAM10 and ADAM17 gene expression in aluminum chloride-induced Alzheimer’s disease rat model. Life Sci. 2021;285:119964.
Kuang X, et al. Neuroprotective effect of ligustilide through induction of α-secretase processing of both APP and Klotho in a mouse model of Alzheimer’s disease. Front Aging Neurosci. 2017;9:353.
Durairajan SSK, et al. Stimulation of non-amyloidogenic processing of amyloid-β protein precursor by cryptotanshinone involves activation and translocation of ADAM10 and PKC-α. J Alzheimers Dis. 2011;25(2):245–62.
Cai Z, et al. Berberine alleviates amyloid-beta pathology in the brain of APP/PS1 transgenic mice via inhibiting β/γ-secretases activity and enhancing α-secretases. Curr Alzheimer Res. 2018;15(11):1045–52.
Ethics approval consent to participate
Consent for publication
There are no competing interests to declare.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Khezri, M.R., Mohebalizadeh, M. & Ghasemnejad-Berenji, M. Therapeutic potential of ADAM10 modulation in Alzheimer’s disease: a review of the current evidence. Cell Commun Signal 21, 60 (2023). https://doi.org/10.1186/s12964-023-01072-w
- Alzheimer’s disease
- Amyloid β
- Natural compounds