Cholinergic forebrain activation improves cognition, boosts neurotrophin receptors, and lowers Aβ42 levels in the cerebral cortex of 5xFAD mice

The biological basis of Alzheimer’s dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms reflecting the neuropathologies surrounding beta amyloid and tau. To shed light on the contributions of these different biological elements, we performed five month intermittent stimulation of the basal forebrain, which projects to the cortical mantle, in 5xFAD Alzheimer’s model mice and wild-type littermates, and subjected mice to behavioral testing and tissue analysis. The 5xFAD mice performed worse in water maze testing than their littermates. Stimulation improved both classes of mice, and removed performance differences between genotypes by the fifth testing day. Stimulated groups had two to four-fold increases in immunoblot measures of each of the neurotrophin receptors tropomyosin receptor kinase A and B. Stimulation also led to lower tissue Aβ 42 and beta amyloid cleavage enzyme 1 in 5xFAD mice. Despite the lack of strong direct projections from the basal forebrain stimulation region to the hippocampus, the hippocampal tissues in stimulated mice had more nerve growth factor receptor, and lower levels of beta secretase for amyloid. These data support a causal relation between forebrain cholinergic pathways and cognitive decline dependent on Aβ 42 . Activation of cholinergic brain pathways improves neurotrophin pathways and reduces Aβ 42 accumulation. The recruitment of both classes of neurotrophin receptors in the process suggests a serine protease cleavage intermediary between cholinergic response and neurotrophin activation.