Targeted neuronal reprogramming rescues memory and neural synchrony in Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and represents a major societal burden. Aging is the strongest risk factor for AD, and partial cellular reprogramming using Yamanaka factors (YFs) has recently emerged as a strategy to counteract age-associated dysfunction. However, the mechanisms by which partial reprogramming ameliorates AD-related phenotypes remain poorly defined. Here, we investigated whether targeted and intermittent expression of YFs in hippocampal neurons restores cognitive function and neural network integrity in the P301S mouse model of tauopathy. We first show that controlled YFs expression in hippocampal neurons increases excitatory synaptic transmission and enhances neural synchrony in GCaMP6-expressing neuronal networks. We then induced intermittent, neuron-specific YFs expression for six months in adult control and P301S mice. This intervention led to a sex-dependent improvement in cognitive and emotional behaviors in P301S mice, accompanied by a reduction in Tau pathology and partial restoration of epigenetic aging markers. At the molecular level, reprogramming restored the composition and signaling of N-methyl-D-aspartate receptor (NMDAR) macro-complexes, including key subunits and AD-associated risk factors such as proline-rich tyrosine kinase 2 (PYK2/PTK2B). Importantly, impaired hippocampal neural synchrony observed in P301S mice was also rescued. Together, these findings demonstrate that targeted, partial in vivo neuronal reprogramming reverses behavioral and network-level deficits in a mouse model of AD and identify NMDAR-associated signaling as a potential mechanistic mediator of this effect.