Elucidating the roles of AMPK isoforms in Alzheimer's Disease Pathogenesis

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Project Summary/Abstract Alzheimer’s disease (AD) is the most common form of dementia in the elderly, and may become a new epidemic in the 21st century in accordance with the rapid growth of the aging population. There is currently no known cure or treatment to stop the progression of AD. Moreover, the basic molecular mechanisms responsible for AD remain elusive. Two key events in AD pathophysiology are impaired capacity of de novo protein synthesis (mRNA translation) and disrupted cellular energy homeostasis. AMP-activated protein kinase (AMPK) acts as a central cellular energy sensor to maintain cellular energy homeostasis. Furthermore AMPK integrates several signaling pathways (including AKT, GSK3, mTORC1, and eEF2) controlling de novo protein synthesis, dysregulation of which is implicated in cognitive syndromes associated with neurodegenerative diseases including AD. Mammalian AMPK is a heterotrimeric protein with a catalytic α subunit and regulatory β/γ subunit. The α subunit of AMPK exists in two isoforms: α1 and α2, and their roles in AD are unknown. By investigating brain tissue from post mortem human AD patients and a transgenic mouse model of AD, I have found that levels of AMPKα1 are dramatically increased while levels of AMPKα2 are decreased. The central hypothesis of the current project is that disruption of AMPK isoform homeostasis represents a key molecular mechanism of AD pathophysiology. Thus, the objective of this project is to determine whether selective AMPK isoform inhibition (and subsequent altering of AMPK isoform homeostasis) alleviates AD-associated deficits in protein synthesis and memory formation. This project will utilize a novel mouse model in which Prkaa1 and Prkaa2 (genes that encode AMPK α1 and α2 subunits, respectively) were removed in excitatory neurons in forebrains and hippocampus late in development, to generate brain- and isoform-specific conditional AMPKα1 and α2 knockout mice (AMPKα1 cKO and AMPKα2 cKO). We have further crossed the heterozygous AMPKα1/2 cKO mice [AMPKα1(+/-) and AMPKα2(+/-)] with Tg19959 AD mouse model (containing two familial AD mutations: K670N and V717F) to generate Tg19959/AMPKα1(+/-) and Tg19959/AMPKα2(+/-) double mutant mice. Using behavioral, electrophysiological, and biochemical methods, the experiments here will 1) elucidate the effects of genetic repression of AMPK isoforms on AD-associated synaptic plasticity impairments; 2) determine the effects of AMPK isoform suppression in learning and memory deficits in AD model mice; and 3) establish whether specific AMPK isoform reduction improves AD pathology, including brain amyloid deposition and de novo protein synthesis impairments. The experimental findings derived from this project will help elucidate a novel mechanism for AD pathophysiology, shedding a light on potentially new diagnostic biomarkers and therapeutic targets.