Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer’s Disease

Abstract

SummaryAbnormalities of the endolysosomal and autophagy systems are found in Alzheimer’s disease, but it is not clear whether defects in these systems are a cause or consequence of degenerative processes in the disease. In human neuronal models of monogenic Alzheimer’s disease, APP and PSEN1 mutations disrupt lysosome function and autophagy, leading to impaired lysosomal proteolysis and defective autophagosome clearance. Processing of APP by γ-secretase is central to the pathogenic changes in the lysosome-autophagy system caused by PSEN1 and APP mutations: reducing production of C-terminal APP by inhibition of BACE1 rescued these phenotypes in both APP and PSEN1 mutant neurons, whereas inhibition of γ-secretase induced lysosomal and autophagic pathology in healthy neurons. Defects in lysosomes and autophagy due to PSEN1 mutations are rescued by CRISPR-knockout of APP. These data demonstrate a key role for proteolysis of the C-terminal of APP by γ-secretase in neuronal dysfunction in monogenic Alzheimer’s disease.

Effects of gene mutation and disease progression on representative neural circuits in familial Alzheimer’s disease

“…The lysosomal-autophagy defects are dependent on APP protein and not independent phenotypes due to either APP or PS1 mutation. Furthermore, PS1 mutant neurons do not have early endosome defects, in contrast with APP mutant neurons [65]. These evidence may partially explain the different effects of APP and PS1 mutation on the neural circuits in our study.…”

“…The bars indicate mean (SD). # 0.025 < P < 0.05, * 0.01 < P < 0.025 function, and autophagy [64][65][66], all of which can affect the properties of neural circuits. The lysosomal-autophagy defects are dependent on APP protein and not independent phenotypes due to either APP or PS1 mutation.…”

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

“…The FAD-associated APP V717I mutant induces the accumulation of enlarged early endosomes in neurons and lysosomes (Hung & Livesey, 2018) Down syndrome (DS) patients have an extra copy of the APP gene and develop an early form of AD. The brain of DS patients shows enlarged endosomes in neurons and accumulation of lysosomes (Cataldo et al, 1996(Cataldo et al, , 2008 PSEN1 Presenilin 1 (PS1) is required for delivery of v-ATPase V0a1 subunit to lysosomes and therefore PS1 deficiency affects lysosomal acidification (Lee et al, 2010) Inhibition of gamma-secretase increases APP-CTF secretion by exosomes (Sharples et al, 2008) Fibroblasts harbouring the FAD-linked A246E PS1 mutation show poor lysosomal acidification (Coffey et al, 2014) Fibroblasts carrying the FAD-linked PS1 mutations A246E, M233T, H163Y, M146L, and L392V have impairement of autophagic protein degradation (Lee et al, 2010) Fibroblasts from patients with p.Leu(381)Phe mutation in PS1 show lysosomal inclusions (Dolzhanskaya et al, 2014) ApoE Mice carrying the AD-associated ApoE4 isoform show dysregulation of endosomal-lysosomal pathways (Nuriel et al, 2017) Humans and mice carrying the APOE4 isoform have lower exosomes biogenesis (Peng et al, 2019) AD patients homozygous for APOE4 show lower autophagic gene products in the brain in comparison to AD patients homozygous for APOE3 allel (Parcon et al, 2018) SORL1 SORL1 is involved in sorting Aβ peptide to lysosomes for degradation (Caglayan et al, 2014).…”

“…For example, fibroblasts carrying presenilin-1 with the FAD p.Leu(381)Phe mutation show lysosomal inclusions (Dolzhanskaya et al, 2014). In addition, fibroblasts carrying the FAD-associated PS1 mutations A246E, M233T, H163Y, M146L, and L392V show impaired autophagic protein degradation (Lee et al, 2010), while human neurons with the PS1 mutations M146I, Y115C, and Intron 4 accumulate late endosomes and clustered lysosomes (Hung & Livesey, 2018).…”

“…The disruption of the interaction between APP and SorlA results in the impairment of lysosomal degradation in the hippocampus of rodents (La Rosa et al, 2015). On the other hand, cortical excitatory neurons generated from iPSC cells derived from individuals with FAD-associated APP V717I mutation have an accumulation of enlarged endosomes and lysosomes (Hung & Livesey, 2018). Besides, the levels of APP and APP-βCTF themselves can contribute to the alterations of endo-lysosomal compartments observed in AD patients (Lauritzen et al, 2016).…”