Moderator of 1 Session
Presenter of 1 Presentation
LOSS OF PRESENILIN FUNCTION CAUSES TAU PHOSPHORYLATION AND AGGREGATION IN MICE
Abstract
Aims
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). The mechanisms by which PSEN mutations affect Aβ are well defined, but the precise role PS/γ-secretase on tau pathology in neurodegeneration independently of Aβ is largely unclear. Here, we aimed to define the cellular mechanisms by which PS regulates tau pathology during neurodegeneration.
Methods
We performed molecular, pathological and behavioral analyses in novel mutant Tau transgenic mice lacking presenilin-1 (PS1) or both PS genes in glutamatergic neurons.
Results
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 associated with altered tau kinases. Interestingly, genetic inactivation of PS1 or both PS genes in a mouse model of frontotemporal dementia expressing mutant human tau exacerbates memory deficits by accelerating phosphorylation and aggregation of tau in excitatory neurons of vulnerable AD brain regions. Remarkably, neurofilament (NF) light chain levels are abnormally accumulated in Tau mice lacking PS. Synchroton 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 PS-deficient Tau mice.
Conclusions
Partial loss of PS/γ-secretase in neurons causes temporal- and spatial-dependent tau aggregation associated with memory and synaptic deficits and neurodegeneration. Our findings show that tau phosphorylation and aggregation are key pathological processes that may underlie neurodegeneration caused by familial AD-linked PS mutations.