Age-dependent neuroinflammation and cognitive decline in a novel Ala152Thr-Tau transgenic mouse model of PSP and AD

Astrid Sydow, Katja Hochgräfe, Stefanie Könen, Daniela Cadinu, Dorthe Matenia, Olga Petrova, Maria Joseph, Frank Johannes Dennissen, Eva-Maria Mandelkow

Mutations of Tau are associated with several neurodegenerative disorders. Recently, the Tau mutation A152T was described as a novel risk factor for frontotemporal dementia spectrum disorders and Alzheimer disease. In vitro Tau-A152T shows a decreased binding to microtubules and a reduced tendency to form abnormal fibers. To study the effects of this mutation we generated a mouse model expressing human full-length Tau with this mutation (hTau40(AT)). At young age (2-3 months) immunohistological analysis reveals pathological Tau conformation and Tau-hyperphosphorylation combined with Tau missorting into the somatodendritic compartment of neurons. With increasing age there is Tau aggregation including co-aggregates of endogenous mouse Tau and exogenous human Tau, accompanied by loss of synapses (especially presynaptic failure) and neurons. From ~10 months onwards the mice show a prominent neuroinflammatory response as judged by activation of microglia and astrocytes. This progressive neuroinflammation becomes visible by in vivo bioluminescence imaging after crossbreeding of hTau40(AT) mice and Gfap-luciferase reporter mice. In contrast to other Tau-transgenic models and Alzheimer disease patients with reduced protein clearance, hTau40(AT) mice show a strong induction of autophagy. Although Tau-hyperphosphorylation and aggregation is also present in spinal cord and motor cortex (due to the Thy1.2 promoter), neuromotor performance is not affected. Deficits in spatial reference memory are manifest at ~16 months and are accompanied by neuronal death. The hTau40(AT) mice mimic pathological hallmarks of tauopathies including a cognitive phenotype combined with pronounced neuroinflammation visible by bioluminescence. Thus the mice are suitable for mechanistic studies of Tau induced toxicity and in vivo validation of neuroprotective compounds.