O2-02-05: Amyloid causes tauopathy by activating GSK3

Abstract

Accumulation of amyloid peptides is the earliest molecular defect in Alzheimer's disease (AD), due to increased production or diminished clearance. Integral to pathology of AD is, by definition, accumulation of protein tau, due to over-phosphorylation resulting in conformational changes and aggregation. The hypothesis that amyloid precedes and induces tau pathology in AD is experimentally supported here, while GSK3 is essential in the underlying mechanisms. We generated two new bigenic mouse models: (i) APP-V717I × Tau-P301L mice (biAT) with combined amyloid and tau-pathology: (ii) GSK3β × Tau-P301L mice (biGT) with tauopathy only. Comparative analysis, including the parental APP-V717I and Tau-P301L strains, yielded important data on pivotal roles of GSK3 in AD pathology. The biAT mice present with progressive, synergistic amyloid and tau pathology most dramatic in CA1/2 and cortex, similar in all aspects to the pathology in AD patients. Remarkably, biAT mice survive longer than parental tau-P301L mice (dead before age 1 year) in close correlation with lesser brain-stem tauopathy (Terwel et al, Am J Pathol, 2008). In biGT mice, the neuronal co-expression of Tau-P301L and GSK3β yields a dramatic forebrain tauopathy, with in older biGT mice “tangles in most forebrain neurons”. Remarkably, no major neuron-loss is observed, demonstrating that tangles are not neurotoxic per se. The biGT mice survive even longer than biAT mice, paralleling their more strongly reduced brainstem tauopathy. The close parallels between biAT and biGT mice, comprises (i) similar pathological phospho-epitopes of protein tau, (ii) similar aggravation of tauopathy by amyloid as by GSK3β with neurofibrillary tangles in hippocampus and cortex; (iii) similar defects in behaviour and cognition. Finally but significantly, GSK3 isozymes are activated in the parental APP-V717I amyloid mice, even at young age, when defects in cognition and LTP occur, but before amyloid deposition. The combined data corroborate that neurofibrillary tangles are not neurotoxic per se, and position GSK3 as major signalling link from amyloid to tauopathy in AD. The models offer wide pre-pathology windows to define molecular signals that act up- and downstream or in parallel with GSK3 isozymes: activation by amyloid, contribution to tau-phosphorylation, and role in cognition defects.