PGC-1α deficiency promotes the generation of Aβ peptide in AD models
It has been suggested that reduced PGC-1α expression in the AD brain strongly correlates with the progression of clinical dementia and neuropathology (Qin et al., 2009), based on the data showing that NR treatment increases PGC-1α expression. Thus it is interesting to know if PGC-1α deficiency might causally promote AD type β-amyloidosis in in vitro and in vivo experimental models. First, we crossed Tg2576 mice with PGC-1α null (PGC-1α−/−) mice (Leone et al., 2005) to generate PGC-1α+/−/APP double transgenic mice, followed by crossing PGC-1α+/−/APP F1 mice with PGC-1α null mice to generate PGC-1α−/−/APP (PGC-1α null/APP) mice. Assessed by ELISA, we found that the homozygous knockout of PGC-1α in PGC-1α−/−/APP mice significantly promoted Aβ neuropathology (reflected by Aβ1–40 and Aβ1–42 levels in the cerebral cortex and hippocampus) by approximately 40%, in comparison with age- and sex-matched APP (Tg2576) mice (Fig. 3A) (n = 3; p < 0.05). Further, in in vitro feasibility studies using primary cortical-hippocampal neuron cultures derived from Tg2576 mice, we found that reducing the cellular levels of PGC-1α by approximately 1.5-fold (data not shown) by infecting cultured cells with an adenoviral PGC-1α silencing shRNA significantly increased the accumulation of β-amyloid Aβ1–40 and Aβ1–42 peptides in the conditioned medium by 1.2-fold or more (Fig. 3B). Collectively, these studies support our working hypothesis that downregulation of PGC-1α in the brain might causally promote amyloid neuropathology, and NR treatment improves the PGC-1α expression, thus reducing the Aβ burden in AD mouse models.