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Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease.

Authors: Pedros, I  Petrov, D  Allgaier, M  Sureda, F  Barroso, E  Beas-Zarate, C  Auladell, C  Pallas, M  Vazquez-Carrera, M  Casadesus, G  Folch, J  Camins, A 
Citation: Pedros I, etal., Biochim Biophys Acta. 2014 Sep;1842(9):1556-66. doi: 10.1016/j.bbadis.2014.05.025. Epub 2014 Jun 2.
Pubmed: (View Article at PubMed) PMID:24887203
DOI: Full-text: DOI:10.1016/j.bbadis.2014.05.025

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 Abeta (1-42) were detected in the brain extracts of the transgenic animals as early as 3 months of age, prior to the Abeta plaque formation (pre-plaque stage). By the early plaque stage (6 months) both the soluble and insoluble Abeta (1-40) and Abeta (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-alpha, 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-1alpha 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-1alpha, 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.


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CRRD Object Information
CRRD ID: 10045934
Created: 2015-06-24
Species: All species
Last Modified: 2015-06-24
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.