Exploring mechanisms of synaptic vulnerability and resilience in Primary Age Related Tauopathy

Abstract

AbstractBackgroundPrimary Age Related Tauopathy (PART) is a sporadic dementia‐related illness, characterized by pathological tau accumulation limited to the hippocampal‐entorhinal region in the absence of Aβ plaques. Studying PART thus presents a unique opportunity to 1) characterize toxic tau species, namely oligomeric (tauO) tau, and to 2) explore molecular mechanisms underlying regional synaptic vulnerability (i.e. hippocampus) and resilience (i.e. neocortex) within a singular tauopathy—such as low‐density lipoprotein receptor 1 (LRP1), recently uncovered as a key mediator of tau uptake and trans‐synaptic spreading.MethodsWe compared levels of tauO, total tau, and LRP1 between the hippocampus and superior medial temporal cortex (SMT) in 7 post‐mortem PART patients. Total homogenate and synaptosomal fractions were prepared for Western Blot; both fractions were probed for total tau (Tau13), and LRP1. TauO were ascribed to high molecular weight tau bands using the total tau probe. p‐tau (AT180) and paired helical filaments (PHF13.6) were also probed in the total homogenate fraction to assess PART neuropathology. The Wilcoxon matched‐pairs signed rank test was utilized to compare regional differences.ResultsWe found elevated levels of p‐tau and PHF in the hippocampus vs. SMT (total homogenate), thus validating previously reported PART neuropathology. We observed a trend towards increased tauO in the hippocampus vs. SMT in PART total homogenate (p=0.11) and synaptosome fractions (p=0.06). Of note, no regional differences were found in total tau levels in either the fractions. In the total homogenate, we found no statistically significant regional differences in LRP1 (p=0.30). Interestingly however, we observed decreased LRP1 in the hippocampus vs. SMT in 6 out of 7 PART patients. On the orher hand, we found no significant differences or notable trends in LRP1 between the hippocampus vs. SMT in the synaptosomal fraction.ConclusionsThis investigation of PART neuropathology is the first to demonstrate accumulation of tauO, restricted to the hippocampus and its synapses. We further report lower levels of LRP1 in the hippocampus of PART patients, a seemingly extra‐synaptic phenomenon, that could potentially mediate regional vulnerability to pathological tau species. Further biochemical and functional assays to characterize tau toxicity and spread are currently under investigation.