Cognitive and GABAergic protection by hAPPSw,Ind and hTauVLW coexpression: a model of Non-Demented with Alzheimer's disease Neuropathology

Alzheimer9s disease comprises amyloid-β (Aβ) and hyperphosphorylated Tau (P-Tau) accumulation, imbalanced neuronal activity, aberrant oscillatory rhythms, and cognitive deficits. Non-Demented with Alzheimer9s disease Neuropathology (NDAN) defines a novel clinical entity with Aβ and Tau pathologies, but preserved cognition. The mechanisms underlying such neuroprotection remain undetermined and animal models are currently unavailable for NDAN. We show that J20/VLW mice, accumulating Aβ and P-Tau, exhibit preserved hippocampal rhythmic activity and cognition, altered in J20 and VLW animals. Furthermore, we show that coexistence with Aβ renders a particular P-Tau signature in hippocampal interneurons. The GABAergic septohippocampal pathway, responsible for hippocampal rhythmic activity, is preserved in J20/VLW mice, in contrast to single mutants. Our data highlight J20/VLW mice as a suitable animal model to understand the mechanisms driving cognitive preservation in NDAN and suggest that a differential P-Tau pattern in hippocampal interneurons prevents GABAergic septohippocampal innervation loss and alterations in local field potentials, avoiding cognitive deficits.