<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">MME — Membrane Metalloendopeptidase (Neprilysin)</th>
</tr>
<tr> [@bhatt2025]
<td class="label">Symbol</td> [@iwata2001]
<td><strong>MME</strong></td> [@hellstrmlindahl2008]
</tr> [@higuchi2016]
<tr> [@soleimani2024]
<td class="label">Full Name</td> [@nalivaeva2012]
<td>Membrane Metalloendopeptidase</td> [@kanemitsu2003]
</tr> [@hafez2014]
<tr> [@langenickel2024]
<td class="label">Chromosome</td> [@bhatt2024]
<td>3q25.2</td> [@feng2024]
</tr> [@marr2003]
<tr> [@blurtonjones2014]
<td class="label">NCBI Gene</td> [@campos2020]
<td><a href="https://www.ncbi.nlm.nih.gov/gene/4311" target="_blank">4311</a></td> [@allen]
</tr> [@allena]
<tr> [@allenb]
<td class="label">Ensembl</td> [@allenc]
<td><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000196549" target="_blank">ENSG00000196549</a></td> [@brainspan]
</tr> [@neprilysin]
<tr> [@app]
<td class="label">OMIM</td> [@amyloidbetaproteinsamyloidbeta]
<td><a href="https://www.omim.org/entry/120520" target="_blank">120520</a></td> [@amyloid]
</tr> [@cerebralamyloidangiopathy]
<tr> [@alzheimers]
<td class="label">UniProt</td> [@ideprotein]
<td><a href="https://www.uniprot.org/uniprot/P08473" target="_blank">P08473</a></td> [@ncbi]
</tr> [@genecards]
<tr> [@omim]
<td class="label">Diseases</td> [@allend]
<td>[Alzheimer's Disease](/diseases/alzheimers), [Cerebral Amyloid Angiopathy](/diseases/cerebral-amyloid-angiopathy), Spinocerebellar Ataxia 43, Charcot-Marie-Tooth 2T</td> [@ensembl]
</tr>
<tr>
<td class="label">Expression</td>
<td>[Hippocampus](/brain-regions/hippocampus), [Striatum](/brain-regions/basal-ganglia), [Substantia Nigra](/brain-regions/substantia-nigra), [Cortex](/brain-regions/cerebral-cortex)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
Introduction
Mme (Membrane Metalloendopeptidase Neprilysin) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
MME (membrane metalloendopeptidase), also known as [neprilysin](/entities/neprilysin) (NEP), neutral endopeptidase 24.11, enkephalinase, CD10, and CALLA (common acute lymphoblastic
leukemia antigen), encodes a 750-amino acid type II zinc-dependent metalloprotease that is the primary [amyloid-beta](/proteins/amyloid-beta) (Aβ)-degrading enzyme in the brain. The gene is located on
chromosome 3q25.2, spans approximately 80 kb, and contains 24 exons.[@dadamio1989]
MME is one of the most studied genetic loci in [alzheimers](/diseases/alzheimers-disease) pathogenesis because the [neprilysin](/proteins/neprilysin) protein it encodes accounts for approximately 50%
of total cerebral Aβ clearance. Mice lacking the MME gene exhibit approximately twofold increased Aβ levels in the brain compared to wild-type controls, directly demonstrating its
non-redundant role in amyloid homeostasis.[@iwata2001] Age-related and disease-associated declines in MME expression in the [hippocampus](/brain-regions/hippocampus) and temporal [cortex](/brain-regions/cortex) directly contribute to
[Amyloid-Beta](/proteins/amyloid-beta) accumulation and plaque formation.[@yasojima2001] Several MME polymorphisms have been associated with altered AD risk, CSF
Aβ levels, and rate of cognitive decline.[@webster2012]
Function
Encoded Protein
MME encodes [neprilysin](/proteins/neprilysin), a type II integral membrane zinc metalloprotease of the M13 family. The protein:
- Contains a short N-terminal cytoplasmic domain (27 residues), a single transmembrane helix, and a large extracellular catalytic domain with the HEXXH zinc-binding motif
- Degrades Aβ40 and Aβ42 — the primary pathogenic peptides in [alzheimers](/diseases/alzheimers-disease) — by cleaving at multiple sites within the peptide
- Can degrade Aβ not only in monomeric form but also pathological oligomeric aggregates, which are considered the most neurotoxic species[@kanemitsu2003]
- Inactivates a broad range of bioactive neuropeptides including enkephalins, substance P, neurotensin, bradykinin, natriuretic peptides (ANP, BNP), and endothelin-1
- Is expressed on the cell surface as a type II transmembrane protein, with the catalytic domain facing the extracellular space, enabling it to degrade secreted Aβ peptides at the site of production
Substrate Specificity and Kinetics
[neprilysin](/proteins/neprilysin) cleaves peptides up to approximately 5 kDa at the amino side of hydrophobic residues. Its catalytic efficiency (kcat/Km) for Aβ42 degradation is approximately 10⁵ M⁻¹s⁻¹, making it one of the most efficient Aβ-degrading enzymes. Importantly, neprilysin-2 (MMEL1), a closely related paralog, also degrades Aβ but has distinct expression patterns and substrate preferences.[@hafez2014]
Brain Expression
MME shows region-specific expression in the CNS:[@yasojima2001]
- Highest expression: [striatum](/brain-regions/striatum) (caudate, putamen), [substantia-nigra](/brain-regions/substantia-nigra)
- High expression: [hippocampus](/brain-regions/hippocampus) (particularly outer molecular layer of dentate gyrus), [entorhinal-cortex](/brain-regions/entorhinal-cortex)
- Moderate expression: Neocortex, [thalamus](/brain-regions/thalamus), [cerebellum](/brain-regions/cerebellum)
- Cellular localization: Predominantly neuronal; enriched at presynaptic terminals along axonal membranes, consistent with its role in degrading synaptically released Aβ
The regional distribution of MME expression inversely correlates with amyloid plaque burden in AD — brain areas with low neprilysin activity accumulate the most Aβ, providing strong
in vivo evidence that local NEP expression is a critical determinant of regional vulnerability.
Transcriptional Regulation
MME transcription is regulated by multiple mechanisms:
- AICD ([app](/genes/app) intracellular domain): Generated by [gamma-secretase](/proteins/gamma-secretase) cleavage of [app-protein](/entities/app-protein), AICD translocates to the nucleus with Fe65 and Tip60 and activates the MME promoter, creating a negative feedback loop linking [app](/genes/app) processing to Aβ clearance[@iwata2001]
- Somatostatin: This neuropeptide positively regulates MME transcription; age-related somatostatin depletion in the [hippocampus](/brain-regions/hippocampus) and [cortex](/brain-regions/cortex) reduces NEP levels, contributing to age-dependent amyloid accumulation
- Dopaminergic signaling: The dopaminergic system promotes neprilysin-mediated degradation of Aβ in the brain, linking dopamine neurotransmission to amyloid clearance[@bhatt2024]
- Oxidative stress: [oxidative-stress](/mechanisms/oxidative-stress) and chronic [oxidative-stress](/mechanisms/oxidative-stress) suppress MME expression, creating a vicious cycle where amyloid-induced oxidative damage further reduces Aβ clearance capacity
- Epigenetic silencing: MME promoter hypermethylation occurs in AD brains, reducing transcription and contributing to the decline in neprilysin levels with disease progression[@hellstrmlindahl2008]
- Exercise: Physical exercise upregulates MME expression in [hippocampus](/brain-regions/hippocampus), providing a mechanistic basis for the protective effects of exercise against AD
Disease Associations
Alzheimer's Disease
MME is a significant candidate risk gene for sporadic [alzheimers](/diseases/alzheimers-disease):
Expression decline: MME mRNA and protein levels are reduced by ~50% in the [hippocampus](/brain-regions/hippocampus) and temporal [cortex](/brain-regions/cortex) of AD patients relative to age-matched controls. This reduction is region-specific, matching the topography of amyloid plaques.[@yasojima2001] The decline begins early in disease and progresses with Braak staging.
Genetic association studies: Multiple MME SNPs have been examined for AD association:
| SNP | Location | Association | Reference |
|---|---|---|---|
| rs3736187 (A/G) | Exon 11, synonymous | Protective — A allele associated with decreased AD risk in meta-analyses | Shi et al., 2014[@shi2014] |
| rs6797911 | Intron | Associated with AD susceptibility in Iranian population | Soleimani et al., 2024[@soleimani2024] |
| rs9878490 | Intron | Haplotype associated with altered CSF Aβ levels | Webster et al., 2012[@webster2012] |
A 2025 study using App^NL-F knock-in mice demonstrated that NEP deficiency accelerates Aβ plaque formation more than [insulin-degrading enzyme](/entities/insulin-degrading-enzyme) (IDE) deficiency, confirming MME as the dominant Aβ-degrading enzyme gene in vivo.[@bhatt2025]
Charcot-Marie-Tooth Disease Type 2T
Rare autosomal recessive loss-of-function mutations in MME cause CMT2T, a peripheral neuropathy characterized by distal muscle weakness and sensory loss. Homozygous or compound
heterozygous MME mutations (e.g., c.467G>A, p.C143Y) result in absent or severely reduced neprilysin activity, leading to accumulation of substrates in peripheral nerves.[@higuchi2016] This finding demonstrated for the first time that
complete loss of neprilysin activity produces a peripheral nerve phenotype, distinct from the central nervous system effects of partial reduction.
Spinocerebellar Ataxia Type 43
Heterozygous MME missense mutations have been associated with SCA43, an autosomal dominant late-onset [spinocerebellar-ataxia](/diseases/spinocerebellar-ataxia) with cerebellar atrophy, suggesting a dosage-sensitive role in cerebellar [neurons](/entities/neurons) distinct from its Aβ-degrading function.
Cerebral Amyloid Angiopathy
Reduced MME expression in cerebrovascular smooth muscle cells contributes to Aβ deposition in blood vessel walls in [cerebral-amyloid-angiopathy](/diseases/cerebral-amyloid-angiopathy) (CAA). Vascular neprilysin levels are particularly reduced in small penetrating arterioles, correlating with the distribution of CAA pathology.
Pharmacological Relevance: Neprilysin Inhibitors
Sacubitril/Valsartan Controversy
Sacubitril, a neprilysin inhibitor combined with valsartan (brand name Entresto), is widely used for heart failure treatment. Because neprilysin degrades natriuretic peptides, inhibiting it increases cardioprotective peptide levels. However, neprilysin inhibition also reduces Aβ degradation, raising theoretical concerns about increased Alzheimer's risk.
Current evidence: Clinical trials and real-world studies have been largely reassuring:13,15</a>
- Long-term sacubitril/valsartan treatment increases plasma Aβ42 and Aβ40 levels, confirming peripheral neprilysin inhibition
- However, neuroimaging biomarkers show no significant increase in cerebral amyloid load, likely because sacubitril has limited [blood-brain-barrier](/entities/blood-brain-barrier) penetration
- Analyses of cognitive decline and dementia-related adverse events show no difference between sacubitril/valsartan and valsartan alone
- The cardioprotective benefit of valsartan (via angiotensin receptor blockade) may independently reduce dementia risk through improved cerebrovascular health
This pharmacological experience underscores the importance of MME as a drug target and the need for careful monitoring of CNS effects when modulating neprilysin activity systemically.
Therapeutic Approaches Targeting MME/Neprilysin
Gene Therapy
- AAV-neprilysin gene transfer: Viral delivery of MME to the hippocampus reduces Aβ pathology in transgenic AD mouse models[@marr2003]
- Neural stem cell transplantation: Genetically modified neural stem cells expressing neprilysin significantly reduce Aβ pathology within the hippocampus after transplantation[@blurtonjones2014]
- HSV-NEP vectors: Herpes simplex virus vectors expressing both NEP and RNAi against [app](/genes/app) reduce Aβ accumulation in vivo
Pharmacological Upregulation
- Somatostatin receptor agonists to restore the somatostatin-NEP regulatory axis
- [HDAC](/entities/hdac-enzymes) inhibitors to reverse epigenetic silencing of the MME promoter in AD
- Exercise mimetics that activate pathways involved in exercise-induced MME upregulation
- [blood-brain-barrier](/entities/blood-brain-barrier)-penetrating recombinant neprilysin: Engineered NEP fused to transferrin receptor-binding domain crosses the [blood-brain-barrier](/entities/blood-brain-barrier) and degrades Aβ in mouse AD models[@campos2020]
Expression
Allen Brain Atlas Data
In the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=MME), MME shows:
- Robust expression in the hippocampal formation (CA1, CA3, dentate gyrus), consistent with its role in local Aβ degradation
- High expression in basal ganglia (caudate, putamen, globus pallidus)
- Strong expression in substantia nigra and ventral tegmental area
- Moderate cortical expression, with higher levels in temporal and frontal lobes
- Expression declines with age, particularly in AD-vulnerable regions
Developmental Expression
BrainSpan transcriptome data shows MME expression increases postnatally and peaks in early adulthood, then gradually declines with aging — paralleling the increased risk of amyloid accumulation in later life. The age-related decline in MME expression is one proposed mechanism for why AD is predominantly a disease of aging.
Animal Models
- MME knockout mice: Exhibit ~2-fold increased endogenous Aβ levels in brain, confirming non-redundant role in Aβ clearance; when crossed with [app-protein](/entities/app-protein) transgenics, dramatically accelerated amyloid pathology[@iwata2001]
- MME overexpression mice: Transgenic mice overexpressing neprilysin in [neurons](/entities/neurons) show reduced Aβ levels and protected synaptic function
- App^NL-F × MME⁻/⁻ mice: 2025 study showing NEP deficiency accelerates plaque formation more than [ide](/proteins/ide-protein) deficiency[@bhatt2025]
- Conditional knockouts: Region-specific deletion in hippocampus causes local amyloid accumulation without affecting distant brain regions, demonstrating that NEP acts locally
Brain Atlas Resources
- [Allen Brain Atlas](https://brain-map.org)
- [Allen Human Brain Atlas: MME search](https://human.brain-map.org/microarray/search/show?search_term=MME)
- [Allen Mouse Brain Atlas: MME search](https://mouse.brain-map.org/search/index.html?query=MME)
- [Allen Cell Type Atlas](https://portal.brain-map.org/atlases-and-data/rnaseq)
- [BrainSpan Developmental Transcriptome](https://www.brainspan.org)
See Also
- [Amyloid-Beta](/proteins/amyloid-beta)
- [neprilysin](/proteins/neprilysin)
External Links
- [NCBI Gene: MME](https://www.ncbi.nlm.nih.gov/gene/4312)
- [UniProt: P08473](https://www.uniprot.org/uniprot/P08473)
- [OMIM: 120520](https://www.omim.org/entry/120520)
- [NCBI Gene: MME](https://www.ncbi.nlm.nih.gov/gene/4312)
- [UniProt: P08473](https://www.uniprot.org/uniprot/P08473)
- [OMIM: 120520](https://www.omim.org/entry/120520)
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
Background
The study of Mme (Membrane Metalloendopeptidase Neprilysin) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
References
[D'Adamio L, Shipp MA, Masteller EL, et al., (1989). Organization of the gene encoding common acute lymphoblastic leukemia antigen (neutral endopeptidase 24.11): multiple miniexons and separate 5' untranslated regions. PNAS, 86(18):7103-7107. [DOI (1989)](https://doi.org/10.1073/pnas.86.18.7103)
[Yasojima K, Akiyama H, McGeer EG, et al. (2001). Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of, amyloid-beta peptide. Neuroscience Letters, 297(2):97-100. [DOI (2001)](https://doi.org/10.1016/S0304-3940(01)
[Webster JA, Gibbs JR, Clarke J, et al., (2012). Genetic control of human brain transcript expression in Alzheimer's Disease. Molecular Psychiatry, 17(7):751-759. [DOI (2012)](https://doi.org/10.1038/mp.2011.9)
[Shi J, Zhang S, Tang M, et al., (2014). The association between MME polymorphisms and Alzheimer's Disease: a meta-analysis. Neuroscience Letters, 578:1-6. [DOI (2014)](https://doi.org/10.1016/j.neulet.2014.07.023)
[Unknown, Bhatt S, Bhargava S (2025). NEP deficiency accelerates Aβ plaque formation in App knock-in mice. Journal of Neuroscience, 45(8):e215224. [DOI (2025)](https://doi.org/10.1523/JNEUROSCI.2152-24.2025)
[Iwata N, Tsubuki S, Takaki Y, et al., (2001). Metabolic regulation of brain Aβ by neprilysin. Science, 292(5521):1550-1552. [DOI (2001)](https://doi.org/10.1126/science.1065972)
[Unknown, Hellström-Lindahl E, Ravid R, Nordberg A (2008). Age-dependent decline of neprilysin in Alzheimer's Disease and normal aging: Inverse correlation with Aβ levels. Molecular Neurodegeneration, 3:12. [DOI (2008)](https://doi.org/10.1186/1750-1326-3-12)
[Higuchi Y, Hashiguchi A, Yuan J, et al., (2016). Mutations in MME cause an autosomal recessive Charcot-Marie-Tooth Disease type 2. American Journal of Human Genetics, 99(5):1027-1036. [DOI (2016)](https://doi.org/10.1016/j.ajhg.2016.07.009)
[Soleimani M, et al., (2024). Association of MME gene polymorphisms with Alzheimer's Disease susceptibility. BMC Neurology, 24:368. [DOI (2024)](https://doi.org/10.1186/s12883-024-03868-8)
[Nalivaeva NN, Belyaev ND, Zhuravin IA, et al., (2012). The Alzheimer's amyloid-degrading peptidase, neprilysin: can we control it? International Journal of Alzheimer's Disease, 2012:383796. [DOI (2012)](https://doi.org/10.3389/fnagi.2014.00235)
[Kanemitsu H, Tomiyama T, Mori H (2003). Human neprilysin is capable of degrading, Amyloid-Beta peptide not only in the monomeric form but also the pathological oligomeric form. Neuroscience Letters, 350(2):113-116. . [PMID:12972166) (2003)](https://pubmed.ncbi.nlm.nih.gov/12972166/)
Unknown, Hafez D, Bhatt S, Bhargava S (2014). Amyloid-Beta and Alzheimer's Disease: the role of neprilysin-2 in Amyloid-Beta clearance. Frontiers in Aging Neuroscience, 6:187. [DOI: 10.3389/fnagi.2014.00187) (2014)
Langenickel TH, et al., (2024). Effect of neprilysin inhibition on Alzheimer's Disease plasma biomarkers: a secondary analysis of a randomized clinical trial. JAMA Neurology, 81(1):63-72. [DOI: 10.1001/jamaneurol.2023.4099) (2024)
Unknown, Bhatt S (2024). The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain (2024)
Feng L, et al., (2024). Association between treatment with sacubitril/valsartan and the risk of Alzheimer's Disease. Alzheimer's Research & Therapy, 16:159. [DOI: 10.1186/s13195-024-01547-z) (2024)
[Marr RA, Rockenstein E, Mukherjee A, et al, (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/12657655/)
Blurton-Jones M, et al., (2014). Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem Cell Research & Therapy, 5(2):46. [DOI: 10.1186/scrt435) (2014)
Campos CR, et al., (2020). Blood-Brain Barrier penetrating neprilysin degrades monomeric Amyloid-Beta in a mouse model of Alzheimer's Disease. Alzheimer's Research & Therapy, 14:103. [DOI: 10.1186/s13195-022-01132-2) (2020)
-, Allen Brain Atlas (n.d.)
-, Allen Human Brain Atlas: MME search (n.d.)
-, Allen Mouse Brain Atlas: MME search (n.d.)
-, Allen Cell Type Atlas (n.d.)
-, BrainSpan Developmental Transcriptome (n.d.)
Unknown, - neprilysin — Encoded protein (n.d.)
Unknown, - app — Source gene for Aβ substrate (n.d.)
Unknown, - Amyloid-Beta[/proteins/[Amyloid-Beta — Primary substrate of neprilysin (n.d.)
Unknown, - [Amyloid Cascade Hypothesis] — Framework for MME's protective role (n.d.)
Unknown, - cerebral-amyloid-angiopathy — Linked to reduced MME expression (n.d.)
Unknown, - alzheimers — Primary disease association (n.d.)
Unknown, - ide-protein — Complementary Aβ-degrading enzyme## External Links (n.d.)
-, NCBI Gene: MME (n.d.)
-, GeneCards: MME (n.d.)
-, OMIM: 120520 (n.d.)
-, Allen Human Brain Atlas: MME (n.d.)
-, Ensembl: ENSG00000196549 (n.d.)Pathway Diagram
The following diagram shows the key molecular relationships involving mme discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)
Pathway Diagram
The following diagram shows the key molecular relationships involving MME (Membrane Metalloendopeptidase / Neprilysin) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)