P4‐076: Amyloid‐B and G‐Protein‐Gated Inwardly‐Rectifying Potassium (Girk/Kir3) Channel in the Rodent Hippocampus

Background: The thesis A causal nexus of mutually interacting elements exists; normal cognition requires their balance whereas imbalance creates AD. Interacting elements include APP, presenilins (PS), mitochondria, mitophagy, unfolded protein response (UPR), Wnt/ beta-catenin, cyclins, Notch, and calcium. In brief detail we describe, first, some effects of individual elements and, second, their mutual interactions.Methods:Literature review (citations will be provided). Results:A. Effects of individual components: Presenilins: Correct protein function requires protein-folding. PS1 plus excessive unfolded proteins, initiate the UPR; ATP is required for chaperones to assist protein-folding. Insufficient ATP from dysfunctional mitochondria causes improper protein-folding, leading to amyloid. PS1wt maintains gamma-secretase as inactive. Mutated/dysfunctional PS1(PSImut) activates gamma-secretase, which cleaves APP to generate A-beta. PS1wt also cleaves Notch1, thus affecting neuronal plasticity and cerebral vascular density. APP and Notch1 are competitive substrates for gamma-secretase so Notch1 activation reduces A-beta generation. High Notch1 levels in AD neurons may exist to improve the known, poor cerebral capillary vascularity in AD.Wnt 5a andWnt 7 signalling regulate adult neurogenesis in the SVZ, and also affect synapses;Wnt 3 affects differentiation of NSCs. Dysfunctional mitochondria in AD, major contributors to neuronal dysfunction, require elimination bymitophagy. Noteworthily, neuronal endocytosis initiates mitophagy before A-beta deposition. Mitophagy engulfs damaged mitochondria into autophagic vacuoles (AV); intermediate vacuoles develop, then fuse with lysosomes for digestion by cathepsins. AD brains showed 20-fold more AVs (they dispose impaired mitochondria, which stimulates biogenesis of normally functioning organelles). Calcium, whether high or low, stimulates autophagy. B. Interactions between elements of the causal nexus: Amyloid deposits in mitochondrial membranes create mitochondrial dysfunctions, decrease mitochondrial biogenesis, and impair neuronal function. A-beta causes low Wnt signaling, reducing neural b-catenin and neuronal viability. Interactions between PS1wt, cyclins and beta-catenin, disturb the neuronal cell cycle.PSImut producesmany impairments:WhereasPS1wt cleaves Notch1, PSImut inhibits Notch1, thereby reducing capillary density; PSImut enhances release of calcium from ER, causing impaired neuronal function; either high or low calcium stimulates mitophagy; PSImut inactivates elements required to promote UPR. Notch1&3 direct astrocyte formation from NHCs. Conclusions:Normal cognition requires balance within a nexus of interacting elements; imbalance would promote AD.