The present study had focused on the behavioral phenotype and gene expression profile of molecules related to insulin receptor signaling in the hippocampus of 3 and 6 month-old APPswe/PS1dE9 (APP/PS1) transgenic mouse model of Alzheimer's disease (AD). Elevated levels of the insoluble Aβ (1-42) were detected in the brain extracts of the transgenic animals as early as 3 months of age, prior to the Aβ plaque formation (pre-plaque stage). By the early plaque stage (6 months) both the soluble and insoluble Aβ (1-40) and Aβ (1-42) peptides were detectable. We studied the expression of genes related to memory function (Arc, Fos), insulin signaling, including insulin receptor (Insr), Irs1 and Irs2, as well as genes involved in insulin growth factor pathways, such as Igf1, Igf2, Igfr and Igfbp2. We also examined the expression and protein levels of key molecules related to energy metabolism (PGC1-α, and AMPK) and mitochondrial functionality (OXPHOS, TFAM, NRF1 and NRF2). 6 month-old APP/PS1 mice demonstrated impaired cognitive ability, were glucose intolerant and showed a significant reduction in hippocampal Insr and Irs2 transcripts. Further observations also suggest alterations in key cellular energy sensors that regulate the activities of a number of metabolic enzymes through phosphorylation, such as a decrease in the Prkaa2 mRNA levels and in the pAMPK (Thr172)/Total APMK ratio. Moreover, mRNA and protein analysis reveals a significant downregulation of genes essential for mitochondrial replication and respiratory function, including PGC-1α in hippocampal extracts of APP/PS1 mice, compared to age-matched wild-type controls at 3 and 6 months of age. Overall, the findings of this study show early alterations in genes involved in insulin and energy metabolism pathways in an APP/PS1 model of AD. These changes affect the activity of key molecules like NRF1 and PGC-1α, which are involved in mitochondrial biogenesis. Our results reinforce the hypothesis that the impairments in both insulin signaling and energy metabolism precede the development of AD amyloidogenesis.

Alzheimer's disease (AD) is characterized by progressive decrease in cognitive function and loss of short-term memory known to be associated with a dysfunction of the cholinergic system. The pathological hallmarks of AD are beta-amyloid (Abeta) plaques and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau. Hypercholesterolemia and disturbances in glucose metabolism are another risk factors. During the last two decades therapeutic strategies were mainly targeting the Abeta hypothesis. As this approach virtually failed to show a significant clinical benefit research on potential therapeutics has been shifted to tau pathology. However, also this approach has as yet not yielded in new therapeutics. Hence, rebalancing the cholinergic input to improve the cognitive symptoms of AD by inhibition of acetylcholine esterase (AChE) is still the only mechanistic target in addition to N-methyl-D-aspartate (NMDA) receptor blockade by memantine that can be addressed by currently approved medications. Despite the fact that the available AChE inhibitors are directed at an identical target they exhibit some pharmacodynamic and pharmacokinetic features that should be considered when used clinically.

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