Cerebral Phospho-Tau Acts Synergistically with Soluble Aβ42 Leading to Mild Cognitive Impairment in AAV-AD Rats

Background: Alzheimer’s disease (AD) is a continuum of events beginning with an increase in brain soluble Aβ342 followed by the appearance of hyperphosphorylated tau (P-tau, asymptomatic stage). Mild Cognitive Impairment (MCI) then appears (prodromal stage). However, the individual contribution of these two soluble proteins in the onset of the first cognitive symptoms remains unclear. Objectives: We sought to understand the specific impact of p-tau on the development of MCI in the AAV-AD rat model, a model of late-onset Alzheimer’s disease (LOAD) predementia. Methods: We specifically reduced the phosphorylation level of tau while leaving Aβ342 levels unchanged using a DYRK1A protein kinase inhibitor, Leucettine L41, in an adeno-associated virus-based Alzheimer’s disease (AAV-AD) rat model. Leucettine L41 was administered by intraperitoneal injection at 20 mg/kg per day in AAV-AD rats from 9 (late asymptomatic phase) to 10 (prodromal phase) months of age. Results: Decreased soluble forms of P-tau induced by chronic administration of Leucettine L41 did not change soluble Aβ342 levels but prevented MCI onset in 10-month-old AAV-AD rats. Conclusions: The present study argues that P-tau is required to induce the development of MCI. Consistent with our previous findings that soluble Aβ342 is also required for MCI onset, the data obtained in the AAV-AD rat model confirm that the transition from the asymptomatic to the prodromal stage may be caused by the combined presence of both soluble brain forms of Aβ342 and p-tau, suggesting that the development of MCI may be the consequence of their synergistic action.