Fig. 11.

Diagram of progression of neuropathology in hTau40^AT mice. Continuous expression and accumulation of hTau40^AT in brain and spinal cord of hTau40^AT mice lead to early pathologic changes at 2–3 months of age, including Tau-phosphorylation, Tau-mislocalization into the somatodendritic compartment and Tau-co-aggregation of endogenous mouse Tau and exogenous hTau40^AT into pretangles. At 3–4 months of age, initial mature tangles (NFTs) are detected by Gallyas silver and ThS staining. Neuroinflammatory processes start from 5 months onwards. Progressive Tau-phosphorylation, Tau-co-aggregation and neuroinflammation likely cause neurotoxic events, resulting in synaptic decay, neurodegeneration and cognitive decline of aged hTau40^AT mice. In parallel, progressive neuroinflammation might alter protein degradation systems, inducing autophagy and reducing proteasome activity in aging hTau40^AT mice. mo: months