INHIBITION OF THE PERINEURONAL NET COMPONENT SEMA3A RESCUES COGNITIVE PERFORMANCE IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is characterized by pathological alterations in the brain, including accumulation of amyloid-β and hyperphosphorylated tau, and progressive cognitive decline. Remarkably, in AD mouse models, cognitive functions can be restored despite the presence of pathology by reactivating neuronal plasticity. This has previously been achieved by enzymatic digestion of chondroitin sulphate proteoglycans (CSPGs). CSPGs are present in the interstitial matrix, around nodes of Ranvier, and within perineuronal nets (PNNs). PNNs are specialized extracellular matrix structures around specific populations of neurons and serve to restrict plasticity and regulate learning and memory. One of the PNN components that contribute to PNN-mediated inhibition of plasticity is Semaphorin 3A (Sema3A). In the brain of amyloid-β-driven AD mice (APP/PS1 mice), we observed an increase in both PNN density and expression of PNN-associated Sema3A. To test whether targeted PNN manipulation can enhance plasticity and restore cognition in AD mice, we interfered with Sema3A signaling in APP/PS1 mice. A secreted variant of the Sema3A receptor neuropilin-1 (referred to as NRP1 bodies) was overexpressed throughout the brain of APP/PS1 mice via adeno-associated viral vectors (AAV-PHP.eB) that cross the blood-brain-barrier. NRP1 bodies act as decoy receptors, competing with endogenous NRP1 for Sema3A binding, thereby attenuating Sema3A signaling. Interestingly, APP/PS1 mice overexpressing NRP1 bodies showed improved recognition memory and cognitive flexibility compared to control APP/PS1 mice. These findings demonstrate that PNNs are altered in the brain of AD mice and identify PNN-associated Sema3A as a promising therapeutic target for counteracting cognitive decline in AD.