PPARgamma, Glucose Metabolism, and Cognitive Decline

adria_cover_finalLightPeroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG) aka the glitazone receptor is a nuclear receptor that regulates adipose tissue and glucose metabolism.

It is increasingly appreciated that the pathophysiology of Alzheimer’s disease involves micro-glial activation and neuroinflammation, dysregulated lipid metabolism as well as glucose homeostasis. For example, some scientists have referred to Alzheimer’s disease as Type III diabetes, implying that elevated blood sugar and insulin resistance adversely affect cognitive function and may be contributory to the pathogenesis of Alzheimer’s disease. Epidemiological studies have revealed that diabetes significantly increases the risk of later developing Alzheimer’s disease.

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a prototypical ligand-activated nuclear receptor that coordinates lipid, glucose and energy metabolism. PPARgamma agonist treatment reduces amyloid beta load, inflammation and reverses disease associated behavioral alterations. In a recent phase II clinical trial, the PPARgamma agonist rosiglitazone improved cognition and memory in patients with mild to moderate AD.

PPAR Modulators Under Clinical Development

Compound Pharmaceutical Company Location Indication Phase Website
DSP-8658 Sunovion Pharmaceuticals Marlborough, MA Alzheimer’s Disease Phase I www.sunovion.com
T3D-959 T3D Therapeutics San Diego, CA Alzheimer’s Disease Phase I completed www.t3dtherapeutics.com
Rosiglitazone _ _ _ _ _
Piaglitazone _ _ _ _ _

Conclusion

PPARs exhibit a plethora of activities that positively affect AD neuropathology. Besides improving the inflammatory status of patients with AD by suppressing pro-inflammatory mediators and enhancing mitochondrial function, direct involvement has been observed in amyloid-beta processing. PPARgamma is a promising therapeutic target in the pharmacological management of neurodegenerative disease.

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