Abstract
Diabetes and obesity have been implicated as risk factors for dementia. However, metabolic mechanisms and associated signalling pathways have not been investigated in detail in frontotemporal dementia. We therefore here characterised physiological, behavioural and molecular phenotypes of 3- and 8-month-old male tau knock-in (PLB2TAU) vs wild-type (PLBWT) mice. Homecage analysis suggested intact habituation but a dramatic reduction in exploratory activity in PLB2TAU mice. Deficits in motor strength were also observed. At 3 months, PLB2TAU mice displayed normal glucose handling but developed hyperglycaemia at 8 months, suggesting a progressive diabetic phenotype. Brain, liver and muscle tissue analyses confirmed tissue-specific deregulation of metabolic and homeostatic pathways. In brain, increased levels of phosphorylated tau and inflammation were detected alongside reduced ER regulatory markers, overall suggesting a downregulation in essential cellular defence pathways. We suggest that subtle neuronal expression of mutated human tau is sufficient to disturb systems metabolism and protein handling. Whether respective dysfunctions in tauopathy patients are also a consequence of tau pathology remains to be confirmed, but could offer new avenues for therapeutic interventions.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, characterised by a progressive loss of memory and decline in cognitive function
Though both pathologies must be present for a diagnosis of AD, it is important to note that neurofibrillary tangles (NFTs) correlate better with cognitive decline and disease duration and tau-only pathology is observed in isolation, for example in frontotemporal dementia (FTD; [1])
The microtubule-associated protein tau is essential for cytoskeletal stability and assembly, its biological activity is regulated by post-translational modifications, e.g. abnormally hyperphosphorylated tau is detrimental to neuronal function and leads to paired helical filaments (PHFs), the main constituents of NFTs
Summary
Alzheimer’s disease (AD) is the most common form of dementia, characterised by a progressive loss of memory and decline in cognitive function. End-stage AD is defined by two extracellular aggregates, β-amyloid and neurofibrillary tangles (NFTs). Though both pathologies must be present for a diagnosis of AD, it is important to note that NFTs correlate better with cognitive decline and disease duration and tau-only pathology is observed in isolation, for example in frontotemporal dementia (FTD; [1]). The microtubule-associated protein tau is essential for cytoskeletal stability and assembly, its biological activity is regulated by post-translational modifications, e.g. abnormally hyperphosphorylated tau is detrimental to neuronal function and leads to paired helical filaments (PHFs), the main constituents of NFTs. Hyperphosphorylation of tau may promote conformational changes, which can lead to seeding and spreading of pathological protein species throughout the brain [2]
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