PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease.

Alzheimer's disease is the most common form of dementia; however, its molecular mechanisms are not fully understood. We recently identified polymeric glycine-arginine-containing (polyGR+) aggregates as a novel type of proteinopathy in AD autopsy brains. Here, we performed a comprehensive analysis to study if polyGR+ aggregates are associated with AD neuropathological changes (ADNC) and clinical features of AD cases. We show polyGR+ aggregates are detected in ~ 60% of AD postmortem brains from three AD cohorts but not age-similar controls or disease controls with primary age-related tauopathy (PART). A subtype of polyGR+ aggregates with a clustered-punctate morphology that is positive for the markers of dystrophic neurites is associated with earlier onset and shortened survival in AD cases. Increased levels of Aβ plaques and phosphorylated tau (pTau) tangles are detected in the hippocampus of AD autopsy brains with high levels of polyGR+ aggregates compared to AD autopsy brains with minimal polyGR+ staining. In addition to ADNC, a subset of polyGR+ aggregates coexists with limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) or Lewy body pathology (LBP). Hippocampal polyGR+ aggregate levels are ~ 3.8- and ~ 3.71-fold higher in late-onset AD cases who experienced stroke or high blood pressure, respectively. In SH-SY5Y cells, hydrogen peroxide treatment which mimics oxidative stress leads to increased levels of polyGR+ proteins produced by the CASP8 GGGAGA repeat expansion, which was recently shown to associate with increased AD risk. In addition, we show the accumulation of pTau induced by CASP8 polyGR+ protein aggregates is elevated upon hydrogen peroxide treatment. In summary, our results demonstrate polyGR+ aggregates are a frequent and understudied type of proteinopathy in AD autopsy brains and that polyGR proteinopathy is associated with ADNC.