The role of Alzheimer's disease risk genes in endolysosomal pathways

Szabo, Marcell; Mishra, Swati; Knupp, Allison; Young, Jessica E.

doi:10.1016/j.nbd.2021.105576

Cited by 39 publications

(28 citation statements)

References 179 publications

(217 reference statements)

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“…Many genes associated with AD risk are involved in endocytosis, including BIN1, PICALM, CD2AP, EPHA1 and SORL1 (Karch and Goate, 2015; Szabo et al, 2021). In addition, whole-exome sequencing performed on early-onset Alzheimer’s disease patients found multiple genes involved in endolysosomal transport (Kunkle et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Tau seeds translocate across the cell membrane to initiate aggregation

Dodd

LaCroix

Valdez

et al. 2022

Preprint

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Neurodegenerative tauopathies, including Alzheimer’s disease and related disorders, are caused by intracellular aggregation of tau protein in ordered assemblies. Experimental evidence suggests that tau assemblies propagate pathology across brain networks. Tau seeds enter cells through endocytosis but must access the cytoplasm to serve as templates for their own replication. The mechanism by which this occurs is unknown. To study tau uptake, we began with a whole-genome CRISPR knockout screen, which indicated a requirement vacuolar H+ ATPase (v-ATPase) components. Treatment with Bafilomycin A1, an inhibitor of the v-ATPase, also reduced tau entry. We next tested direct modifiers of endolysosomal trafficking. Dominant-negative Rab5a expression uniquely decreased tau uptake, as did temporary cold temperature during tau exposure, consistent with a primary role of endocytosis in tau uptake. However, despite reducing tau uptake, these interventions all paradoxically increased intracellular seeding. Consequently, we generated giant plasma membrane vesicles (GPMVs), which cannot undergo endocytosis, and observed that tau fibrils and monomer translocated into the vesicles, in addition to TAT peptide, whereas transferrin and albumin did not. In every case, tau required binding to heparan sulfate proteoglycans (HSPGs) for cell uptake, seeding, or GPMV entry. These findings are most consistent with direct translocation of tau seeds across the lipid bilayer, a novel mechanism of entry into the cytoplasm.

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Section: Discussionmentioning

confidence: 99%

Tau seeds translocate across the cell membrane to initiate aggregation

Dodd

LaCroix

Valdez

et al. 2022

Preprint

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“…Recent studies demonstrate that oxidative phosphorylation is markedly dysregulated in the brain in a mouse model of DS and AD [ 65 ]. Indeed, mitochondrial bioenergetic dysfunction and associated defects in protein processing have been already implicated in many forms of neurodegeneration [ [66] , [67] , [68] , [69] , [70] , [71] , [72] ]. In this context, it is interesting to note that Kanaumi and colleagues have previously detected a marked increase in CBS-positive astrocytes around senile plaques in adults with DS [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Overproduction of hydrogen sulfide, generated by cystathionine β-synthase, disrupts brain wave patterns and contributes to neurobehavioral dysfunction in a rat model of down syndrome

et al. 2022

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“…Note that the first two papers, and our later discussion of the effects of fAD mutations in PSEN1 and PSEN2, link these genes to normal functioning of the cellular endolysosomal system. Many of the late onset AD risk loci discovered by genome-wide association studies (GWAS) are also important for endolysosomal system function [81,82]. Indeed, the strongest genetic risk factor for sporadic (non-familial) AD, the 4 allele of APOE (APOE4), reduces lysosomal acidification relative to the 3 allele [83] (in common with fAD mutations in APP [28] and the presenilins [84]).…”

Section: The Explanatory Power Of Increased Ctf Levels As the Ad-cau...mentioning

confidence: 99%

An Alternative View of Familial Alzheimer’s Disease Genetics

Lardelli¹

2023

Preprint

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A probabilistic and parsimony-based view of available genetics data is presented to argue that Hardy and Higgins’ amyloid cascade hypothesis is valid but is commonly misinterpreted to support, incorrectly, the primacy of the amyloid beta peptide (Aβ) in driving Alzheimer’s disease pathogenesis. Similar means are used to argue that the pathological effects of familial Alzheimer’s disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in APP cleavage to produce different ratios of Aβ length. Instead, increase in the activity of the bCTF (C99) fragment of APP is likely the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5’ iron responsive element (IRE). Familial Alzheimer’s disease (fAD) mutations in PSEN1 and PSEN2 likely affect the stability of presenilin holoprotein and/or γ-secretase multimers with consequences for γ-secretase activity and other important cellular functions. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of “pseudo-hypoxia” being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern (DAMP) enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease. We also discuss fascinating, but largely ignored, data on presenilin biology that may be important in understanding presenilins’ central role in familial Alzheimer’s disease.

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The role of Alzheimer's disease risk genes in endolysosomal pathways

Cited by 39 publications

References 179 publications

Tau seeds translocate across the cell membrane to initiate aggregation

Tau seeds translocate across the cell membrane to initiate aggregation

Overproduction of hydrogen sulfide, generated by cystathionine β-synthase, disrupts brain wave patterns and contributes to neurobehavioral dysfunction in a rat model of down syndrome

An Alternative View of Familial Alzheimer’s Disease Genetics

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