This mouse study used AAV-mediated neuronal expression of wild-type asynWT, mutant asynE46K, mutant tauA152T, or asynE46K/tauA152T in APPNL-G-F/MAPT double knock-in (amyloid) and MAPT-only (control) mice, induced either post-plaque (6 months) or pre-plaque (3 months), with longitudinal open-field behavior assessed at baseline, 3, and 6 months post-transduction, followed by neuropathology and neuroinflammation analyses at endpoint.
Post-plaque induction in amyloid mice doubled total asyn (~2-fold vs ~1.5-fold in controls) and boosted phospho-asyn+ neurons (~20% vs ~10% in controls); tauA152T-driven phospho-tau+ neurons reached ~12% in amyloid vs ~3% in controls. Triple pathology (asynE46K/tauA152T in amyloid mice) produced the strongest hyperlocomotion and anxiety-like behavior. TauA152T uniquely drove LGALS3+ glial activation in white-matter fiber tracts regardless of amyloid status. Pre-plaque induction yielded robust pathologies (~1.8-fold asyn, ~1.5-fold tau over endogenous) with minimal amyloid-dependent amplification.
- No cognitive or motor-specific behavioral assays were included, limiting interpretation of functional consequences beyond open-field metrics. - Repeated open-field testing may have introduced habituation effects that confound longitudinal behavioral measurements. - Only tauA152T was tested; wild-type tau and other pathogenic tau variants were not run in parallel, so findings may not generalize to all tau variants.
These preclinical findings suggest that amyloid stage at the time of additional proteinopathy onset critically shapes downstream pathology burden and behavioral outcomes, arguing for stage-aware, multi-target treatment strategies in mixed dementias (e.g., Lewy body dementia with AD co-pathology). LGALS3+ white-matter glial activation driven by tauA152T may represent a tractable biomarker or therapeutic target in carriers of this tau risk variant.
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