Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau

Abstract

Neurofibrillary lesions of abnormal Tau are hallmarks of Alzheimer´s disease and frontotemporal dementias. Our regulatable (Tet-OFF) mouse models of tauopathy express variants of human fulllength Tau in the forebrain (CaMKIIα promoter) either with mutation ΔK280 (pro-aggregant) or ΔK280/I277P/I308P (anti-aggregant). Co-expression of luciferase enables in vivo quantification of gene expression by bioluminescence imaging. Pro-aggregant mice develop synapse loss and Tau pathology including missorting, phosphorylation and early pretangle formation, whereas antiaggregant mice do not. We correlated hippocampal Tau pathology with learning/memory performance and synaptic plasticity. Pro-aggregant mice at 16 months of gene expression exhibited severe cognitive deficits in Morris water-maze and in passive-avoidance paradigms, whereas anti-aggregant mice were comparable to controls. Cognitive impairment of pro-aggregant mice was accompanied by loss of hippocampal LTP in CA1 and CA3 areas and by a reduction of synaptic proteins and dendritic spines, although no neuronal loss was observed. Remarkably, memory and LTP recovered when pro-aggregant Tau was switched-OFF for ∼4 months, Tau phosphorylation and missorting were reversed, and synapses recovered. Moreover soluble and insoluble pro-aggregant hTau40 disappeared while insoluble mouse Tau was still present. This study links early Tau pathology without neurofibrillary tangles and neuronal death to cognitive decline and synaptic dysfunction. It demonstrates that Tau-induced impairments are reversible after switching-OFF pro-aggregant Tau. Therefore our mouse model may mimic an early phase of AD when the hippocampus does not yet suffer from irreversible cell death but cognitive deficits are already striking. It offers potential to evaluate drugs with regard to learning and memory performance. § corresponding author: Eva-Maria Mandelkow,

Adenosine A 1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

“…Transgenic proaggregant Tau is expressed at 83% of wild-type Tau levels, whereas antiaggregant Tau is expressed at 50% of wild-type Tau levels in 30 d in vitro (DIV30) organotypic slices (Fig. 1E), which is approximately threefold less as has been found in the in vivo Tau transgenic mouse brain (6). The quantitative difference between proaggregant and antiaggregant Tau could be partially Significance Tau-driven neurotoxicity occurs in multiple neurodegenerative diseases that have a severe impact on families and the society at large.…”

“…The proaggregant transgenic mice have aberrantly phosphorylated human Tau-ΔK280, although the relation between these posttranslational modifications and Tau toxicity is poorly understood (6). Therefore, to differentiate between toxic and nontoxic modifications of Tau, we compared the phosphorylation status of Tau in proaggregant (ΔK280) and antiaggregant (ΔK280-PP) transgenic organotypic hippocampal slices ( Fig.…”

“…The markers described so far did not reveal any clear mode of action of toxic proaggregant Tau despite the functional impairment reported previously in transgenic mice (6). We therefore designed a quantitative PCRbased miniscreen of key genes known to be (up-)regulated at the mRNA level as a result of specific stressors serving as markers for insults (Table S3).…”

“…In transgenic mice expressing human Tau with the ΔK280 mutation, the Tau protein is missorted into the somatodendritic compartment, (hyper)phosphorylated, and folded into a pathological conformation (MC-1 epitope) (5). These mice are still functionally impaired from ∼12 mo onward despite the absence of neurofibrillary tangles (6). Here, we use this transgenic human Tau model (ΔK280, proaggregant) in parallel with its antiaggregant counterpart (ΔK280-PP line) where Tau cannot aggregate because of Ile-toPro mutations that serve as β-sheet breakers (7).…”

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…However, both hTau‐A152T and hTau‐WT mice had age‐dependent increases in synaptic transmission strength and decreases in paired‐pulse facilitation at the mossy fiber/CA3 pyramidal cell synapse. In contrast, synaptic transmission and facilitation were unaltered or reduced at this synapse in hTau mice bearing FTDP‐17 mutations (P301L and ∆K280) that strongly promote tau aggregation 36, 78, 79, 80, 81. Whether and how these phenotypic differences relate to specific conformations and assemblies of tau 82 remains to be determined.…”