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.