β-Amyloid Induces Pathology-Related Patterns of Tau Hyperphosphorylation at Synaptic Terminals

Abstract

A synergy between β-amyloid (Aβ) and tau appears to occur in Alzheimer disease (AD), but the mechanisms of interaction, and potential locations, are little understood. This study investigates the possibility of such interactions within the cortical synaptic compartments of APP/PS1 mice. We used label-free quantitative mass spectrometry to study the phosphoproteome of synaptosomes, covering 2400 phosphopeptides and providing an unbiased survey of phosphorylation changes associated with amyloid pathology. Hyperphosphorylation was detected on 36 synaptic proteins, many of which are associated with the cytoskeleton. Importantly, tau is one of the most hyperphosphorylated proteins at the synapse, upregulated at both proline-directed kinase (PDK) sites (S199/S202, S396/S404) and nonPDK sites (S400). These PDK sites correspond to well-known pathological tau epitopes in AD patients, recognized by AT8 and PHF-1 antibodies, respectively. Hyperphosphorylation at S199/S202, a rarely examined combination, was further validated in patient-derived human synaptosomes by immunoblotting. Global surveys of upregulated phosphosites revealed 2 potential kinase motifs, which resemble those of cyclin-dependent kinase 5 (CDK5, a PDK) and casein kinase II (CK2, a nonPDK). Our data demonstrate that, within synaptic compartments, amyloid pathology is associated with tau hyperphosphorylation at disease-relevant epitopes. This provides a plausible mechanism by which Aβ promotes the spreading of tauopathy.

Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice

“…We further observed the consequences of blocking the brain lymphatic pathway on brain Aβ, Tau and phosphorylated tau aggregation . Both 6E10‐immunopositive diffuse plaques and thioflavin‐S positive fibrillar plaques noticeably increased in the cerebral cortex and hippocampus of APP/PS1‐ligation mice, compared with APP/PS1‐sham mice (6E10: cortex, P = 0.0489; hippocampus, P = 0.0488; thioflavin‐S: cortex, P = 0.0443; hippocampus, P = 0.0189; Figure A–C).…”

A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain

“…pS416 and pS422 were both previously described as being phosphorylated on synaptic tau in both human patients and mouse models [65][66][67]. pS422 in particular has been targeted by a passive immunization strategy in triple transgenic mice (TauPS2APP mice, [65]), and data from the same mouse model suggest that this phosphorylation event is promoted by the presence of amyloid plaques [66].…”

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

“…Autophagy vacuole accumulation in distal end of neurons imposes neuronal autophagy stress in AD [47]. These synaptic autophagy vacuoles and aggregates clearance failure imposes synaptic toxicity resulting in impaired synaptic plasticity and memory dysfunction ( Figure 2) [90,91].…”