Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration

Abstract

A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer’s disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296–390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

“…Indeed, this profile of selective deficits may provide further evidence of the FTD relevant phenotype of the PLB2 Tau mice, expressing prominent semantic deficits earlier than spatial memory deficits, potentially reflecting a vulnerability of higher neuronal processes (semantic vs. spatial learning) and regions (prefrontal vs. temporal) relevant to FTD tau pathology. Similar findings have been reported in the THY-Tau22 mouse model, where non-spatial memory was affected prior to spatial memory, although only a modest reduction in STFP was observed (Van der Jeugd et al, 2013) and are in agreement with results in L66 (Melis et al, 2015) and V337M models (Tamemura et al, 2001). …”

“…Interestingly, several models with relatively low transgene expression (0.1-2 fold increase), such as a V337M model (Tamemura et al, 2001) as well as our recently published line 66 (L66) mouse model (Melis et al, 2015) are without deficits in spatial learning despite evident tau pathology. The preservation of basic hippocampal function was also recently observed in a non-transgenic rat model of FTD, where the intra-hippocampal delivery of recombinant hTau induced cognitive impairments related to cognitive flexibility rather than spatial memory (Koss et al, 2015).…”

“…The preservation of basic hippocampal function was also recently observed in a non-transgenic rat model of FTD, where the intra-hippocampal delivery of recombinant hTau induced cognitive impairments related to cognitive flexibility rather than spatial memory (Koss et al, 2015). In contrast, the selective expression of mutant hTau within the entorhinal cortex (de Calignon et al, 2012) or the expression of paired helical filament derived Tau truncation products (Hrnkova et al, 2007; Line 1 in Melis et al, 2015) appears to preferentially engage AD relevant pathological mechanisms, recapitulating Braak stage progression of tau pathology and selectively affecting spatial (hippocampal) aspects over those underlying emotional processing and motor function. Thus, dependent on variables such as the tau species and level of expression, differential pathological processes and regional effects may occur which align phenotypes with the symptomology of AD vs. FTD.…”

Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

“…Initially, pathology is seen within the transentorhinal cortex before spreading to the hippocampus and then to neocortical regions . We have recently reported a novel mouse expressing truncated but non-mutated Tau 296-390, which genuinely replicates pathology of Braak staging and presents with a predominantly cognitive phenotype [37]. Although it remains unclear how this expression pattern is realised, pathology seems to invade other brain regions following their connectivity pathways in a prion-like fashion.…”

Tau aggregation inhibitors: the future of Alzheimer’s pharmacotherapy?

“…[16] The in vivo effects of MTC and TRx0237 (5-75 mg/kg orally for 3-8 weeks) were compared in two novel mouse models overexpressing different human tau-protein constructs (L1 and L66). [37] Both MTC and TRx0237 dose-dependently rescued the learning impairment and restored behavioral flexibility in a spatial problem-solving water-maze task in L1 (minimum effective dose: 35 mg MT/kg for MTC, 9 mg MT/ kg for TRx0237) and corrected motor learning in L66 (effective doses: 4 mg MT/kg). [18] Both compounds reduced the number of tau-reactive neurons, particularly in the hippocampus and entorhinal cortex in L1 and in a more widespread manner in L66.…”