PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Abstract

Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.Aβ | BACE1 | growth factor | inflammation | neurodegeneration

Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms

“…PET brain scans reveal decreased radiolabeled glucose uptake into neurons and biochemical analyses demonstrate reduced activity of mitochondrial enzymes involved in oxidative phosphorylation and the TCA cycle [6]. Recent findings suggest that mitochondrial biogenesis is impaired in AD as indicated by reduced levels of the transcriptional regulator of mitochondrial biogenesis PGC1-α [34]. Consequently, dysfunctional mitochondria accumulate in neurons resulting in reduced cellular ATP levels and excessive ROS production which can exacerbate mitochondrial damage, leading to the aberrant amyloidogenic processing of APP and pTau and subsequent formation of AD-defining Aβ plaques and neurofibrillary tangles [10, 35].…”

“…Consistent with a role of impaired PGC-1α in AD pathology, upregulation of PGC-1α can inhibit AD progression. In APP23 transgenic mice, LV (lentiviral vector)-hPGC-1α injected in the hippocampus and cortex areas decreased Aβ plaques and improved spatial and recognition memory, possibly through downregulation of β-secretase [34]. …”

Therapeutic Potential of FGF21 in Alzheimer’s Disease

“…Exogenous human PGC-1α (hPGC-1α) expressed in primary neurons from the Tg2576 mouse of AD decreased Aβ generation by reducing BACE1 transcription which was dependent on PPAR γ [83] [84]. In accordance with this result, gene delivery of hPGC-1α in the brain of transgenic APP23 mice reduced amyloid deposition, which correlated with a decrease in BACE1 expression [85]. These findings suggest that FGF21 may reduce Aβ generation by decreasing BACE1 expression, as illustrated in Figure 1.…”

Targeting Alzheimer's disease with gene and cell therapies

“…Activation of transcription factor PPAR gamma (Peroxisome proliferator-activated receptor gamma, PPARc), a nuclear receptor regulating fatty acid and glucose metabolism, by PPARc coactivator 1 alpha (PGC-1a), an adaptor protein, could yield useful therapeutic effects. Viral PGC-1a gene delivery reduced Ab deposition by lowering BACE1 expression levels, improving spatial and recognition memory in an AD mouse model [13]. In addition, the ectopic expression of PGC-1a increased neprilysin expression (see next section), which may have contributed to the lowered Ab pathology.…”