Elsevier Inc. potential AD miRNA neurofibrillary tangles microglia neuroinflam mation hyperphosphorylated Tau AD susceptibility genes Abeta toxic Abeta ---| mitochondria dynamics pathway Abeta interacting partners ---- toxic Abeta senile amyloid plaques gamma-secretase ---> toxic Abeta App Apoe ---> lipoprotein metabolism tau kinases ---> hyperphosphorylated Tau Bace1 gamma-secretase ---> App Bace1 ---> App Apoe ---> cholesterol transport Bace1 ---> Abeta gamma-secretase ---> Abeta Abeta degrading enzymes ---> toxic Abeta Abeta degrading enzymes ---> Abeta Mapt tau phosphatases ---> Mapt tau kinases ---> Mapt Apoe astrocyte toxic Abeta ---| respiratory complex IV microtubule cytoskeleton assembly Mapt ---> microtubule cytoskeleton assembly oxidative stress --+> tau kinases oxidative stress ---| tau phosphatases proteostatic stress oxidative stress potential AD miRNA ---> Alzheimer's Disease (AD) cholesterol transport lipoprotein metabolism ApoE4 ---> impaired cholesterol/lipid, impaired vesicle endocytosis AD susceptibility genes ---> synaptic dysfunction, synapse loss, cognitive decline AD susceptibility genes ---> impaired cholesterol/lipid, impaired vesicle endocytosis cerebral hypoperfusion ---> synaptic dysfunction, synapse loss, cognitive decline glucose hypometabolism ---> synaptic dysfunction, synapse loss, cognitive decline hyperphosphorylated Tau ---| mitochondria dynamics pathway hyperphosphorylated Tau ---| respiratory complex I impaired cholesterol/lipid, impaired vesicle endocytosis ApoE4 Psen1 Psen2 downregulated miRNA upregulated miRNA upregulated target translation downregulated target translation neurovascular coupling AD susceptibility genes ---> neuroinflam mation cerebral hypoperfusion mitochondria dynamics pathway ---> synaptic dysfunction, synapse loss, cognitive decline LTP toxic Abeta ---| LTP toxic Abeta ---| neurovascular coupling toxic Abeta --+> neuroinflam mation toxic Abeta toxic Abeta --+> LTD LTD LTD ---> synaptic dysfunction, synapse loss, cognitive decline synaptic dysfunction, synapse loss, cognitive decline hyperphosphorylated Tau ---> synaptic dysfunction, synapse loss, cognitive decline glucose hypometabolism oxidative stress ---| glycolysis pathway astrogliosis tau kinases tau phosphatases Abeta degrading enzymes Abeta interacting partners respiratory complex IV respiratory complex I electron transport chain pathway mitochondria dynamics pathway glycolysis pathway gamma-secretase Alzheimer's Disease (AD) early-onset, familial AD AD type 4 AD type 1 late-onset, sporadic AD AD type 2