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

• Published in: Biochimica et biophysica acta Vol. 1842; no. 9; pp. 1556 - 1566
• Main Authors: Pedrós, Ignacio, Petrov, Dmitry, Allgaier, Michael, Sureda, Francesc, Barroso, Emma, Beas-Zarate, Carlos, Auladell, Carme, Pallàs, Mercè, Vázquez-Carrera, Manuel, Casadesús, Gemma, Folch, Jaume, Camins, Antoni
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2014
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Protein Precursor - physiology; Amyloidogenic Proteins; Animals; APPswe/PS1dE9; Biomarkers - metabolism; Blotting, Western; Disease Models, Animal; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Immunoenzyme Techniques; Insulin receptor; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Presenilin-1 - physiology; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tau; Tau; Mitochondria; Insulin receptor; Alzheimer's disease; Hippocampus; APPswe/PS1dE9
• ISSN: 0925-4439; 0006-3002
• 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 6month-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 3months of age, prior to the Aβ plaque formation (pre-plaque stage). By the early plaque stage (6months) 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). 6month-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 6months 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. [Display omitted] •A down-regulation of genes involved in insulin pathways was found in APP/PS1 mice.•mRNA and protein analysis reveals a significant reduction in PGC-1α levels in the hippocampus of APP/PS1 mice.•6month-old APP/PS1 mice were glucose intolerant.•CDK5 was activated in the hippocampus of APP/PS1 mice, at 3 and 6months.