Home > Articles > Published articles > Loss of presenilin function enhances tau phosphorylation and aggregation in mice |
Date: | 2021 |
Abstract: | Mutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer's disease (AD). Although the mechanisms by which these mutations affect Aβ are well defined, the precise role PS/γ-secretase on tau pathology in neurodegeneration independently of Aβ is largely unclear. Here we report that neuronal PS deficiency in conditional knockout (cKO) mice results in age-dependent brain atrophy, inflammatory responses and accumulation of pathological tau in neurons and glial cells. Interestingly, genetic inactivation of presenilin 1 (PS1) or both PS genes in mutant human Tau transgenic mice exacerbates memory deficits by accelerating phosphorylation and aggregation of tau in excitatory neurons of vulnerable AD brain regions (e. g. , hippocampus, cortex and amygdala). Remarkably, neurofilament (NF) light chain (NF-L) and phosphorylated NF are abnormally accumulated in the brain of Tau mice lacking PS. Synchrotron infrared microspectroscopy revealed aggregated and oligomeric β-sheet structures in amyloid plaque-free PS-deficient Tau mice. Hippocampal-dependent memory deficits are associated with synaptic tau accumulation and reduction of pre- and post-synaptic proteins in Tau mice. Thus, partial loss of PS/γ-secretase in neurons results in temporal- and spatial-dependent tau aggregation associated with memory deficits and neurodegeneration. Our findings show that tau phosphorylation and aggregation are key pathological processes that may underlie neurodegeneration caused by familial AD-linked PSEN mutations. |
Grants: | Ministerio de Ciencia e Innovación SAF2016-80027-R Ministerio de Ciencia e Innovación PID2019-106615RB-100 Instituto de Salud Carlos III CB06/05/0042 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-749 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/FI_B00326 |
Note: | The online version contains supplementary material available at 10.1186/s40478-021-01259-7. |
Note: | Altres ajuts: This study was funded by ALBA Synchrotron project 2019013256 (to CAS and CMSF). CMSF and PSM are supported by predoctoral fellowships from UAB (PIF B16P0050). |
Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Subject: | Alzheimer's disease ; Memory ; Neurofilament ; Presenilin ; Γ-secretase ; Tau ; Synapse ; Β-sheet aggregation |
Published in: | Acta neuropathologica communications, Vol. 9 (September 2021) , art. 162, ISSN 2051-5960 |
20 p, 3.5 MB |