Coexistence of amyloid-β and Tau hyperphosphorylation rescues cognitive and electrophysiological deficiencies in a mouse model of Alzheimer’s disease

Alzheimer’s disease hallmarks include amyloid-β peptide (Aβ) and hyperphosphorylated Tau (P-Tau), abnormalities in hippocampal oscillatory rhythms, imbalance of neuronal activity, and cognitive deficits. J20 and VLW mice, accumulating Aβ and P-Tau, respectively, show imbalanced neuronal activity and cognitive impairments. Here we analyzed mice simultaneously accumulating Aβ and P-Tau (J20/VLW). No changes in Aβ load or in P-Tau in pyramidal cells were observed in J20/VLW animals compared to respective single transgenic models. Conversely, the density of hippocampal interneurons accumulating pThr205 and pSer262 Tau was higher in J20/VLW than in VLW mice. The GABAergic septohippocampal (SH) connection specifically innervates hippocampal interneurons, modulating hippocampal electrophysiology. Contrarily to previous results showing an important reduction of GABAergic SH innervation in J20 and VLW mice, here we demonstrate that the GABAergic SH connection is preserved in J20/VLW animals. Furthermore, our findings indicate that hippocampal theta rhythms, markedly diminished in J20 and VLW mice, are partially rescued in J20/VLW animals. Moreover, the simultaneous presence of Aβ and P-Tau rescues Aβ-associated recognition memory deficits in J20/VLW mice. Altogether, these data suggest that a differential Tau phosphorylation pattern in hippocampal interneurons protects against loss of GABAergic SH innervation, preventing alterations in local field potentials and avoiding cognitive deficits.