PGC-1α overexpression exacerbates β-amyloid and tau deposition in a transgenic mouse model of Alzheimer's disease

Abstract

The peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) interacts with various transcription factors involved in energy metabolism and in the regulation of mitochondrial biogenesis. PGC-1α mRNA levels are reduced in a number of neurodegenerative diseases and contribute to disease pathogenesis, since increased levels ameliorate behavioral defects and neuropathology of Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. PGC-1α and its downstream targets are reduced both in postmortem brain tissue of patients with Alzheimer's disease (AD) and in transgenic mouse models of AD. Therefore, we investigated whether increased expression of PGC-1α would exert beneficial effects in the Tg19959 transgenic mouse model of AD; Tg19959 mice express the human amyloid precursor gene (APP) with 2 familial AD mutations and develop increased β-amyloid levels, plaque deposition, and memory deficits by 2-3 mo of age. Rather than an improvement, the cross of the Tg19959 mice with mice overexpressing human PGC-1α exacerbated amyloid and tau accumulation. This was accompanied by an impairment of proteasome activity. PGC-1α overexpression induced mitochondrial abnormalities, neuronal cell death, and an exacerbation of behavioral hyperactivity in the Tg19959 mice. These findings show that PGC-1α overexpression exacerbates the neuropathological and behavioral deficits that occur in transgenic mice with mutations in APP that are associated with human AD.

Keywords: Tg19959 mice; behavior; cell death; mitochondria.

Figure 1.

PGC-1α overexpression promoted amyloid plaque deposition in Tg19959 mice. A) Congo red staining of Tg19959 and Tg19959xPGC-1α mouse brains. B, C) Amyloid plaque burden (B) and plaque number (C) in the cerebral cortex and hippocampus of Tg19959 mice (n=6) and Tg19959xPGC-1α littermates (n=6). D) Dot blots of Aβ fibrils using OC in the cerebral cortex of Tg19959 mice (n=6) and Tg19959xPGC-1α littermates (n=6). Quantifications are expressed as a percentage of control (control Tg19959 mice). PGC-1α overexpression increased amyloid plaque burden and number as well as Aβ fibrils in Tg19959 mice. *P < 0.05; unpaired t test.

Figure 2.

PGC-1α overexpression increased soluble Aβ and tau levels in Tg19959 mice. A, B) Aβ_1–42 (A) and Aβ_1–40 (B) levels by ELISA in Tg19959 mice (n=6) and Tg19959xPGC-1α littermates (n=6). C) Western blots of PS1 in Tg19959 mice (n=5) and Tg19959xPGC-1α littermates (n=7). D) Western blots of tau using CP13 antibody in Tg19959 mice (n=6) and Tg19959xPGC-1α littermates (n=6). Quantifications are expressed as ratios to β-actin. PGC-1α overexpression resulted in increased Aβ_1–42 and CP13 levels in Tg19959 mice. *P < 0.05; unpaired t test.

Figure 3.

PGC-1α overexpression induced cell death in Tg19959 mice. A) NeuN staining of wild-type, PGC-1α, Tg19959, and Tg19959xPGC-1α mouse brains. B, C) Neuronal cell count in the cerebral cortex (B) and hippocampus (C) of wild-type (n=4), PGC-1α (n=4), Tg19959 mice (n=7), and Tg19959xPGC-1α littermates (n=6). There is a significant reduction of neuronal cells in Tg19959xPGC-1α mice relative to Tg19959 littermates. *P < 0.05; Fisher's PLSD test.

Figure 4.

PGC-1α overexpression reduced mitochondrial enzyme activities in Tg19959 mice. Enzymatic activity of citrate synthase (A), complex I (B), and succinate dehydrogenase (C) in wild-type (n=14), PGC-1α (n=10), Tg19959 (n=6), and Tg19959xPGC-1α (n=5) mice. Enzymatic activities of citrate synthase, complex I, and succinate dehydrogenase were decreased in Tg19959xPGC-1α as compared to Tg19959 mice. *P < 0.05; Fisher's PLSD test.

Figure 5.

PGC-1α overexpression inhibited proteasomal activity in Tg19959 mice. Caspase-like (A), chymotrypsin-like (B), and trypsin-like (C) activities of the proteasome system in wild-type (n=5), PGC-1α (n=5), Tg19959 (n=5), and Tg19959xPGC-1α (n=5) mice. Proteasome activity was reduced by PGC-1α overexpression. *P < 0.05; Fisher's PLSD test.

Figure 6.

PGC-1α overexpression exacerbated behavioral deficit in Tg19959 mice. A) Distance traveled during the open field test in wild-type (n=14), PGC-1α (n=12), Tg19959 (n=9), and Tg19959xPGC-1α (n=6) mice. B) Percentage of time spent freezing during the contextual fear-conditioning test in wild-type (n=14), PGC-1α (n=12), Tg19959 (n=8) and Tg19959xPGC-1α (n=6) mice. PGC-1α overexpression increased hyperactivity in Tg19959 mice in the open field. In addition, PGC-1α overexpression did not improve memory deficits in Tg19959 mice. *P < 0.05; Fisher's PLSD test.