Optimizing endogenous signaling pathway activity to enhance cognitive resilience

The intricate workings of signaling pathways are well-established with regard to neurodevelopment. Yet, the implications of these pathways for sustaining brain health and resilience during the aging process are not clear. The Hedgehog (Hh) pathway is a system of particular interest due to its dual role in both early development and its lesser-known functions in adult tissue regulation and repair. Their previous research has demonstrated roles of the Hh pathway beyond embryonic development, indicating its active involvement in the regeneration of adult tissues. More recently, they have uncovered that stimulating the Hh pathway in elderly mice significantly boosts their spatial memory, evidenced by their performance in complex maze tests. Additionally, they have observed an increase in the levels of NAAG—a neurotransmitter linked to cognitive ability—using magnetic resonance spectroscopy. Hh pathway activation in aged mice also induced pro-cognitive metabolic changes including ketosis (reduced glucose, elevated ketone bodies). Their proposal aims to establish the cell types and molecular mechanisms that mediate these cognitive improvements. They further aim to apply our recently developed pathway-activating nanobody to precisely activate the Hh pathway, to the specific cells and tissues relevant to cognitive function in aging.