Effect of AMPKα2 knockdown on Alzheimer's pathogenesis and cognitive deficits in young Tg19959 mice.

Abstract

AMP-activated protein kinase (AMPK) is a cellular energy censor that has been implicated in Alzheimer's disease (AD). The catalytic α isoforms (α1 and α2) of AMPK are normally expressed in a homeostatic equilibrium but are differentially expressed in AD brains, with α2 expression significantly decreased compared to controls. AMPK dysregulation may be an early feature of AD that promotes accelerated cognitive decline through its roles in protein synthesis regulation, metabolism, autophagy, and mitochondrial biogenesis. The early loss of the α2 isoform may exacerbate or accelerate disease progression in the preclinical stage. AMPKα2 was conditionally knocked down in excitatory forebrain neurons in the Tg19959 AD mouse model to create a heterozygous AMPKα2/Tg19959 double mutant. At 3-5 months of age, before cognitive impairments become evident, the mice were subjected to the Morris Water Maze (MWM) and Novel Object Recognition (NOR) task that measures hippocampus-dependent spatial learning and memory. In addition, Golgi staining, immunohistochemistry, and transmission electron microscopy of the hippocampus were performed. The double mutant AMPKα2/Tg19959 mice showed significant memory impairments in both the MWM and NOR task compared to wild type, Tg19959, and α2/Cre littermates. The AMPKα2/Tg19959 double mutant mice also showed significant decreases in post-synaptic density size and in the number of polyribosomes. Differences in spine morphology and amyloid plaque deposition were also observed. AMPKα2 knockdown in a "pre-symptomatic" AD mouse model leads to accelerated cognitive deficits and disruption of protein synthesis regulatory mechanisms. Taken together, these findings suggest that reduction of AMPKα2 may exacerbate or accelerate cognitive decline and AD pathogenesis. This finding could provide a future therapeutic target for the treatment of AD.