Targeting adult-born neurons to correct early deficits in pattern separation in the Tg2576 mouse model of Alzheimer's disease.

Hippocampal adult neurogenesis in mammals generates a unique population of immature granule neurons that play a crucial role in memory, learning and spatial processing. In both Alzheimer's disease (AD) patients and mouse models, this neurogenic capacity of the dentate gyrus is reduced. Mouse models of AD have shown that hippocampal adult neurogenesis is altered early in the course of the disease, contributing to hippocampal-dependent memory impairments. Early stages of AD are also associated with mitochondrial dysfunction in adult-born neurons. While mitochondria have emerged as key regulators of adult neurogenesis, they have been found to be dysfunctional in AD context and to contribute to neurodegenerative diseases. In this study, we investigated the timing and nature of memory deficits in Tg2576 mice, a model of AD, focusing on tasks that depend on hippocampal neurons born in adulthood. We found that Tg2576 mice exhibit early deficits in pattern separation tasks. Notably, adult-born neurons in Tg2576 mice show reduced connectivity and mitochondrial content along with the first memory deficits. To mitigate these defects, we used NeuroD1, a potent neuronal transcription factor, to enhance the development of adult-born neurons in Tg2576 mice. Overexpression of NeuroD1 restored both mitochondrial content and spine density in these neurons to levels comparable to those in control mice. In addition, this intervention restored pattern separation performance in Tg2576 mice, highlighting the potential of strategies targeting mitochondria to correct adult neurogenesis-related memory deficits in the early stages of AD.