Fornix Stimulation Enhances Neurovascular Plasticity in Alzheimer's Mouse Model

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 DESCRIPTION (provided by applicant): Current understanding of Alzheimer's disease focuses on accumulation of amyloid and tau proteins, enhanced disease progression with vascular factors (i.e., APoE), a large reduction in metabolism and substrate/energy supply to the brain, significant changes in neurovascular coupling, neuronal damage leading to memory and cognitive abnormalities, cholinergic cell loss, and diffuse brain atrophy. Though a large number of treatments are in trials, the underlying basis of Alzheimer's disease remains unclear. Thus, similar to dopamine replacement therapy for Parkinson's disease, the clinical focus for Alzheimer's disease has been to treat symptoms (i.e., memory) rather than the underlying cause. Since reduced central cholinergic function is prominent in Alzheimer's disease, current human treatment focuses on acetylcholinesterase inhibition for improved memory. Further, a preliminary trial showed encouraging results for enhancing cholinergic cell function and memory loss in Alzheimer's patients using nerve growth factor [NGF] gene therapy into nucleus basalis. Another symptomatic approach has been to enhance memory using deep brain stimulation [DBS] applied to the fornix, currently in being tested in a randomized trial. However, fornix stimulation has also been noted to show widespread metabolic changes in the brain. Though the focus of this DBS approach has been on memory enhancement, fornix and septal stimulation also induces cholinergic stimulation, which can affect blood vessel reactivity and neurovascular coupling and improve metabolism throughout the brain. We hypothesize that fornix DBS stimulation is causing both enhanced memory through hippocampal stimulation and secondary septal stimulation of cholinergic nuclei, affecting neurovascular coupling and blood flow. Septal stimulation would lead to diffuse cholinergic enhancement of hippocampal function, causing changes in excitatory transmission, neurovascular coupling and enhanced substrate/metabolic supply to the brain, likely improving the widespread vascular changes noted in Alzheimer's disease. We propose to study both physiological and vascular effects of fornix/septal stimulation at different time points of development in a progressive, mouse model of Alzheimer's disease that shows a clear deterioration with representative histological changes (i.e., plaques and tangles) over months [CVN-AD] in comparison to the control animals with knockout of the background nitric oxide synthetase (iNOS: NOS2-/-).