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P4‐203: Asparagine endopeptidase cleaves amyloid precursor protein and promotes amyloidogenesis in Alzheimer's disease
Author(s) -
Zhang Zhentao,
Song Mingke,
Liu Xia,
Kang Seong Su,
Duong Duc M.,
Seyfried Nicholas T.,
Cao Xuebing,
Cheng Liming,
Sun Yi,
Yu Shan-Ping,
Levey Allan I.,
Ye Keqiang
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.08.031
Subject(s) - genetically modified mouse , amyloid precursor protein , chemistry , senile plaques , microbiology and biotechnology , proteolysis , amyloid (mycology) , alzheimer's disease , p3 peptide , protein aggregation , biochemistry , transgene , biology , medicine , disease , enzyme , inorganic chemistry , gene
catabolism have been identified, including insulin degrading enzyme, neprilysin (NEP), endothelin-converting enzyme -1 (ECE-1) and ECE-2. While it is commonly assumed that Ab catabolism is ubiquitous and redundant, evidence supports that Ab degrading enzymes may degrade unique pools of Ab. For instance, NEP, ECE-1 and ECE-2 cannot compensate for the loss of function of one another and they are active in different cellular locations. While NEP degrades mostly extracellular Ab, ECE-1 and ECE-2 are found inside Ab-producing vesicles, either in recycling endosomes (thus regulating secretion) or along the endosomal/lysosomal pathway. To understand better the in vivo significance of Ab catabolism compartmentalization, we have initiated a systematic characterization of the distribution of Ab degrading enzymes in brain.Methods: To identify the neuronal populations that express ECE-1, ECE-2 and NEP in mouse cortex and hippocampus, we combined fluorescence immunohistochemistry with multiplex fluorescence in situ hybridization. Results: NEP expression was confined to a subpopulation of neurons sparsely distributed throughout cortex and hippocampus. By immunohistochemistry, we found that the majority of NEP expressing neurons was also parvalbumin-positive (PV+). ECE-2 mRNAwas enriched in another population of GABAergic interneurons, characterized by the expression of the neuropeptide somatostatin (SST+). Consistent with the possible role in modulating synaptic Ab secretion, ECE-1 was more broadly expressed and found associated with some cholinergic fibers. Conclusions: Our results, combined with previous findings that NEP and ECE-2 knockout mice have significant elevations in endogenous Ab levels, suggest that PV+ and SST+ interneurons are major contributors to Ab catabolism. Moreover, the fact that NEP and ECE-2 degrade Ab in specific subcellular compartments indicates that Ab metabolism may vary substantially among different neuronal populations. Finding the Ab degrading enzymes and neuronal types that modulate the most pathological pool(s) of Ab may guide the development of more targeted and effective therapies.