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Fig. 3 | Molecular Neurodegeneration

Fig. 3

From: Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors

Fig. 3

Intrinsic and extrinsic factors dysregulating the endolysosomal flux promote progression to EOAD and LOAD, respectively. APP proteolysis is dysregulated in AD, as shown for instance for familial/early onset AD-associated mutations in PSEN genes. FAD-PSEN2 and some -PSEN1 mutations favor a late-endosomal and lysosomal localization of the respective γ-secretase complexes, driving an increased processing of APP into Aβ peptides. Other PSEN1 and PSEN2 FAD mutations shift the intrinsic cleavage functions of the complex, generating more Aβ42 rather than Aβ40. LOAD risk factors, on the other hand, entail the not-optimal working of different cellular mechanisms, e.g. the endolysosomal flux, making dysregulations to be build-up until they also start to impact other mechanisms. Hence, an elevation in the intracellular Aβ pools can originate from two factors: intrinsic ones (mutations linked with APP processing enzymes) and extrinsic ones (variants linked to a dysfunction or lower flux in the endolysosomal system, e.g. trapping γ-secretases in endosomes). While the intrinsic mutations drive FAD/EOAD, the extrinsic variants cause an increased risk of developing LOAD. Both ultimately lead to the characteristic AD clinical phenotype and pathology

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