Amyloid-β and phosphorylated-tau accumulation in retrosplenial cortex of young Alzheimer's disease model: Impact on network activity

Background The retrosplenial cortex (RSC) is a cortical area that functions as a key component of the core network of brain regions involved in cognitive functions such as episodic memory, navigation, and planning. The RSC is capable of theta rhythm generation and, like the hippocampus, could be compromised in neurological diseases such as Alzheimer's disease (AD). Importantly, detecting early changes in RSC of transgenic animals could be translated into non-invasive biomarkers that can detect preclinical stages of AD and related dementias. Objective Our aim in the present study was to evaluate molecular and functional alterations in the RSC of very young 3xTg-AD mice (1-month-old). Methods Immunohistochemistry, anterograde viral tracer using an adeno-associated virus, western blotting, and electrophysiology were all carried out. Results Our results show significant accumulation of intracellular amyloid-β (Aβ) and hyperphosphorylated tau (pTau) in principal neurons from 1-month-old 3xTg-AD mice, which correlates with GSK3β activation and tau phosphorylation at serine 396. Coincidentally, oscillatory activity from the RSC is altered in the young 3xTg-AD mice. Specifically, we found that theta frequency is significantly higher in the transgenic animals. Conclusions In summary, our results suggest that the early accumulation of intracellular Aβ may affect the excitability of the RSC network, possibly due to changes in pTau resulting from GSK3β activation.