The microtubule-associated protein tau is implicated in various neurodegenerative diseases including Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, which are characterized by intracellular accumulation of hyperphosphorylated tau. Mutations in the tau gene MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). In the human central nervous system, six tau isoforms are expressed, and imbalances in tau isoform ratios are associated with pathology. To date, few animal models of tauopathy allow for the potential influence of these protein isoforms, relying instead on cDNA-based transgene expression. Using the P1-derived artificial chromosome (PAC) technology, we created mouse lines expressing all six tau isoforms from the human MAPT locus, harbouring either the wild-type sequence or the disease-associated N296H mutation on an endogenous Mapt−/− background. Animals expressing N296H mutant tau recapitulated early key features of tauopathic disease, including a tau isoform imbalance and tau hyperphosphorylation in the absence of somatodendritic tau inclusions. Furthermore, N296H animals displayed behavioural anomalies such as hyperactivity, increased time in the open arms of the elevated plus maze and increased immobility during the tail suspension test. The mouse models described provide an excellent model to study the function of wild-type or mutant tau in a highly physiological setting.Tauopathies are a group of neurodegenerative diseases showing characteristic deposits of the microtubule-associated protein tau in the form of intracellular neurofibrillary tangles in the central nervous system. Alzheimer's disease (AD) is the most common tauopathy as well as the most prevalent neurodegenerative disorder worldwide. However, while AD patients' brains are characterised by tauopathic neuropathology, a genetic association of AD with the MAPT locus has not been unequivocally established [1][2][3][4][5] . In 1998, several groups showed that mutations in the MAPT gene are sufficient to cause a rare familial neurodegenerative disorder termed frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [6][7][8][9] . The MAPT locus is also strongly associated with the sporadic tauopathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) which is likely explained by haplotype-specific regulation of alternatively-spliced exons [10][11][12][13] . More recently, a multitude of gene association and genome-wide association studies (GWAS) have identified MAPT as a highly significant genetic risk factor for sporadic Parkinson's disease (PD), despite the lack of obvious tau tangles in the majority of PD patients [14][15][16][17][18] . More recently, imbalances in tau isoform ratios and rod-like tau aggregates have been described in Huntington's disease 19 . In summary, the association of tau with several common neurodegenerative diseases either in the form of pathological inclusions, or as a genetic risk factor, demonstrates that t...

Reduced cerebrovascular response to neuronal activation is observed in patients with neurodegenerative disease. In the present study, we examined the correlation between reduced cerebrovascular response to visual activation (ΔCBFVis.Act) and subclinical cognitive deficits in a human population of mid-sixties individuals without neurodegenerative disease. Such a correlation would suggest that impaired cerebrovascular function occurs before overt neurodegenerative disease. A total of 187 subjects (age 64–67 years) of the Metropolit Danish Male Birth Cohort participated in the study. ΔCBFVis.Act was measured using arterial spin labelling (ASL) MRI. ΔCBFVis.Act correlated positively with cognitive performance in: Global cognition (p = 0.046), paired associative memory (p = 0.025), spatial recognition (p = 0.026), planning (p = 0.016), simple processing speed (p < 0.01), and with highly significant correlations with current intelligence (p < 10−5), and more complex processing speed (p < 10−3), the latter two explaining approximately 11–13% of the variance. Reduced ΔCBFVis.Act was independent of brain atrophy. Our findings suggest that inhibited cerebrovascular response to neuronal activation is an early deficit in the ageing brain and associated with subclinical cognitive deficits. Cerebrovascular dysfunction could be an early sign of a trajectory pointing towards the development of neurodegenerative disease. Future efforts should elucidate if maintenance of a healthy cerebrovascular function can protect against the development of dementia.

No abstract