Neprilysin

Neprilysin, also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an is_associated_with::enzyme that in humans is encoded by the MME gene. Neprilysin is a is_associated_with::zinc-dependent is_associated_with::metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including is_associated_with::glucagon, is_associated_with::enkephalins, is_associated_with::substance P, is_associated_with::neurotensin, is_associated_with::oxytocin, and is_associated_with::bradykinin. It also degrades the is_associated_with::amyloid beta peptide whose abnormal misfolding and aggregation in is_associated_with::neural tissue has been implicated as a cause of is_associated_with::Alzheimer's disease. Synthesized as a membrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the is_associated_with::Golgi apparatus to the cell surface.

Neprilysin is expressed in a wide variety of tissues and is particularly abundant in kidney. It is also a common is_associated_with::acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). This protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL.

Hematopoetic progenitors expressing CD10 are considered "common lymphoid progenitors", which means they can differentiate into T, B or natural killer cells. CD10 is of use in hematological diagnosis since it is expressed by early B, pro-B and pre-B lymphocytes, and by lymph node is_associated_with::germinal centers. Hematologic diseases in which it is positive include ALL, is_associated_with::angioimmunoblastic T cell lymphoma, is_associated_with::Burkitt lymphoma,  is_associated_with::chronic myelogenous leukemia in blast crisis (90%),  is_associated_with::diffuse large B-cell lymphoma (variable),  follicular center cells (70%),  is_associated_with::hairy cell leukemia (10%), and myeloma (some). It tends to be negative in is_associated_with::acute myeloid leukemia, is_associated_with::chronic lymphocytic leukemia, is_associated_with::mantle cell lymphoma, and is_associated_with::marginal zone lymphoma. CD10 is found on non-T ALL cells, which derive from pre-B lymphocytes, and in germinal center-related non-Hodgkin lymphoma such as Burkitt lymphoma and follicular lymphoma, but not on leukemia cells or lymphomas, which originate in more mature B cells.

Amyloid beta regulation
Neprilysin-deficient knockout mice show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain, providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be the is_associated_with::rate-limiting step in amyloid beta degradation, it has been considered a potential therapeutic target; compounds such as the is_associated_with::peptide hormone is_associated_with::somatostatin have been identified that increase the enzyme's activity level. One hypothesis for the strong dependence of Alzheimer's incidence on age focuses on the declining production of somatostatin in the brains of elderly people, which thus depresses the activity of neprilysin and promotes aggregation of unprocessed amyloid beta. Declining neprilysin activity with increasing age may also be explained by is_associated_with::oxidative damage, known to be a causative factor in Alzheimer's disease; higher levels of inappropriately oxidized neprilysin have been found in Alzheimer's patients compared to cognitively normal elderly people.

Signaling peptides
Neprilysin is also associated with other biochemical processes, and is particularly highly expressed in is_associated_with::kidney and is_associated_with::lung tissues. Inhibitors have been designed with the aim of developing is_associated_with::analgesic and is_associated_with::antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as is_associated_with::enkephalins, is_associated_with::substance P, is_associated_with::endothelin, and is_associated_with::atrial natriuretic factor.

Associations have been observed between neprilysin expression and various types of is_associated_with::cancer; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer is_associated_with::biomarker studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as is_associated_with::metastatic is_associated_with::carcinoma and some advanced is_associated_with::melanomas, neprilysin is overexpressed; in other types, most notably is_associated_with::lung cancers, neprilysin is downregulated, and thus unable to modulate the pro-growth is_associated_with::autocrine signaling of cancer cells via secreted peptides such as mammalian homologs related to is_associated_with::bombesin. Some plant extracts (methanol extracts of is_associated_with::Ceropegia rupicola, is_associated_with::Kniphofia sumarae,  is_associated_with::Plectranthus cf barbatus, and an aqueous extract of is_associated_with::Pavetta longiflora) were found able to inhibit the enzymatic activity of neutral endopeptidase.

Inhibitors

 * is_associated_with::Sacubitril (AHU-377), a component of is_associated_with::LCZ696
 * is_associated_with::Omapatrilat
 * is_associated_with::RB-101
 * is_associated_with::UK-414,495

Immunochemistry
CD10 is used in clinical pathology for diagnostic purpose.

In lymphomas and leukemias

 * is_associated_with::Acute lymphoblastic leukemia (ALL) cells are CD10+.
 * is_associated_with::Follicular lymphoma (follicle centre cell lymphoma) are CD10+.
 * Burkitt Lymphoma cells are CD10+.
 * CD10+ diffuse large B cell lymphoma (CD10+ DLBLC)
 * Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor, but CD10+, is_associated_with::BCL2+tumors could have poorer survival. For some authors, CD10 expression in DLBCL does not influence survival.
 * is_associated_with::Angioimmunoblastic T cell lymphoma (AITL) are CD10+ and distinguishes AITL from other T cell lymphomas (CD10−)
 * Some benign T cells can be CD10+

In epithelial tumors

 * is_associated_with::Clear cell renal cell carcinoma (Clear cell RCC)
 * CD10+ distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers. Chromophobe carcinoma and oncocytoma are CD10−.


 * is_associated_with::Pancreatic tumors
 * is_associated_with::Solid pseudopapillary tumours are CD10+.
 * CD10+ differentiates is_associated_with::mucinous cystic neoplasms (CD10+/CK20+) from is_associated_with::intraductal papillary mucinous neoplasm of branch duct type (CD10−/CK20-).


 * is_associated_with::Cutaneous tumors
 * CD10 may differentiate is_associated_with::basal cell carcinoma (CD10 epithelial staining) from is_associated_with::trichoblastoma (CD10 peritumoral stromal staining), basal cell carcinoma with follicular differentiation (CD10 stromal and epithelial staining) and is_associated_with::squamous cell carcinoma (strong stromal staining).
 * CD10 differentiates CD10+ is_associated_with::atypical fibroxanthoma from CD10− spindle cell is_associated_with::melanoma and sarcomatoid is_associated_with::squamous cell carcinoma.


 * is_associated_with::Urothelial tumors express CD10 (42-67%).
 * CD10 expression is strongly correlated with high tumor grade and stage in urothelial carcinoma of the bladder. CD10 may be associated with tumor progression in bladder cancer pathogenesis.

In other tumors

 * CD10 expression might be one of the characteristics of müllerian system-derived neoplastic mesenchymal cells.
 * Normal endometrial stroma
 * is_associated_with::Endometrial stromal sarcoma (ESS) are CD10+ (is_associated_with::Smooth muscle tumors are usually CD10−, but can be CD10+
 * is_associated_with::Malignant müllerian mixed tumor (MMMT)
 * is_associated_with::Müllerian adenosarcoma
 * is_associated_with::Uterine high-grade leiomyosarcoma
 * is_associated_with::Uterine rhabdomyosarcoma


 * is_associated_with::Vascular tumors
 * is_associated_with::Epithelioid hemangioendothelioma are mostly CD10+.
 * is_associated_with::Hemangioblastoma is usually CD10− (metastatic is_associated_with::renal cell carcinoma is CD10+)