PPARɣ Activation Rapidly Ameliorates Amyloid Pathology and Restores Cognition in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the progressive loss of cognition and memory. The pathological hallmarks of AD include extracellular amyloid deposits and intra-neuronal neurofibrillary tangles. Progression of the disease is associated with a disruption of Aβ homeostasis and accumulation and deposition of Aβ in the brain parenchyma, initiating a robust microglial-mediated immune response that leads to the production of pro-inflammatory cytokines, chemokines and reactive nitrogen and oxygen species which are deleterious to the CNS. Despite the abundance of activated microglia surrounding plaques, they are inefficient in clearing fibrillar Aβ deposits. It is thought that activating mechanisms that facilitate Aβ clearance will alleviate disease related pathophysiology and be of great therapeutic utility for the treatment of Alzheimer’s disease.The peroxisome proliferator activated receptor-ɣ (PPARɣ), is a ligand activated nuclear receptor, which regulates lipid and glucose homeostasis in the body and exhibits potent anti-inflammatory actions. Activation of PPARγ has been shown to reduce brain Aβ levels and ameliorate AD related cognitive deficits in animal models of AD. However, the mechanisms through which PPARγ attenuates AD related pathophysiology have yet to be elucidated. We have shown that activation of another nuclear receptor, LXRα, facilitates the proteolytic degradation of Aβ in an ApoE-dependent mechanism through induction of target genes, ABCA1 and ApoE. ABCA1 regulates cholesterol efflux via lipidation of ApoE and this process augments the degradation of soluble Aβ species. Importantly, PPARγ activation induces the expression of LXRα and its targets ApoE and ABCA1, metabolically linking these pathways.We demonstrate that PPARɣ activation using the synthetic agonist, Pioglitazone (Actos™) enhances the proteolytic degradation of Aβ in microglia and astrocytes by utilizing the PPAR-LXR-ApoE linked pathway in the brain. PPARɣ mediated intracellular degradation of Aβ is dependent on expression of ApoE and LXR. Furthermore, an acute (9 day) treatment of APP/PS1 mice with pioglitazone, rapidly increased brain levels of ABCA1 and ApoE, decreased amyloid deposition and ameliorated AD-related cognitive deficits. The reduction in plaque deposition was paralleled with an increase in amyloid-laden microglia and astrocytes in the parenchyma of treated animals. Significantly, pioglitazone treatment of APP/PS1 animals polarized CNS microglia from a “classical” to an “alternative” activation state, reducing glial activation, re-engaging the phagocytic machinery and facilitating the clearance of fibrillar Aβ deposits. Together our data demonstrates an important role for PPARɣ activation in facilitating the clearance of both soluble and fibrillar species of Aβ and provides a mechanistic explanation for how PPARɣ agonists reduce AD-related pathophysiology.