The microglial lysosomal system in Alzheimer’s disease: guardian against proteinopathy

ABSTRACTWe previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimer’s disease AD pathogenesis. Here we shed new light on pathogenic mechanisms by which MT5-MMP controls APP processing and the fate of amyloid beta peptide (Aβ), its precursor C99 and C83. We found in HEK carrying the APP Swedish familial mutation (HEKswe) that MT5-MMP-mediated processing of APP that releases the soluble 95 kDa form (sAPP95), was hampered by the removal of the C-terminal non-catalytic domains of MT5-MMP. Catalytically inactive MT5-MMP variants increased the levels of Aβ and promoted APP/C99 sorting in the endo-lysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, the deletion of which caused a strong degradation of C99 by the proteasome, preventing Aβ accumulation. These findings reveal novel mechanisms for MT5-MMP control of APP metabolism and C99 fate involving proteolytic and non-proteolytic actions mainly mediated by the C-terminal part of the proteinase.

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Alzheimer’s disease and the autophagic-lysosomal system

Neuroscience Letters ◽

10.1016/j.neulet.2018.05.017 ◽

2019 ◽

Vol 697 ◽

pp. 49-58 ◽

Cited By ~ 15

Author(s):

Kyung Min Chung ◽

Nancy Hernández ◽

Andrew A. Sproul ◽

Wai Haung Yu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lysosomal System

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Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene

International Journal of Molecular Sciences ◽

10.3390/ijms222413633 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13633

Author(s):

Luisa Benussi ◽

Antonio Longobardi ◽

Cemile Kocoglu ◽

Matteo Carrara ◽

Sonia Bellini ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Frontotemporal Lobar Degeneration ◽

Lewy Body ◽

Lewy Body Disease ◽

Neurocognitive Disorders ◽

Coated Vesicle ◽

Loss Of Function ◽

Lysosomal System

Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.

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