PPAR-gamma at the Juncture of Alzheimer's Disease and Metabolic Stress

Organizers: Neil Upton, GlaxoSmithKline; Aaron Chuang, GlaxoSmithKline

Speakers: Suzanne De La Monte, Brown University; Giulio M. Pasinetti, Mount Sinai School of Medicine; Nigel Greig, National Institute on Aging; Anthony Akkari, GlaxoSmithKline

Abstracts

Brain Insulin Deficiency and Insulin Resistance in Alzheimer's Disease: Potential Role of PPAR Agonist Treatment and Prevention of Neurodegeneration
Suzanne M. de la Monte, MD, MPH
Rhode Island Hospital

Alzheimer's Disease (AD) is marked by tau hyperphosphorylation/nitrosylation, neuritic dystrophy, cell loss, and AƒÒ-APP deposits in plaques and cerebral vessels. These characteristic structural lesions are accompanied by mitochondrial dysfunction, energy imbalance, oxidative stress, and activation of pro-death signaling. Analysis of human postmortem brains linked the molecular and pathological lesions in AD to major impairments in: 1) insulin and insulin-like growth factor (IGF) gene expression; 2) expression and binding of the insulin and IGF receptors; 3) neuronal survival signaling; and 4) acetylcholine homeostasis, and showed that each of these abnormalities increases with progression of AD. The co-existence of insulin/IGF deficiency and insulin/IGF resistance suggests that AD represents a brain-specific form of diabetes, i.e. Type 3 diabetes that can occur independent of either Type 1 or Type 2 diabetes. We generated an experimental animal model in which intracerebral Streptozotocin (ic-STZ) was used to deplete brain and not pancreatic insulin/IGF, and produce neurodegeneration that resembles human AD. Although the ic-STZ-injected rats did not have hyperglycemia, and pancreatic architecture and insulin immunoreactivity were similar to control, their brains were reduced in size and exhibited neurodegeneration with neuronal loss, gliosis, and increased immunoreactivity for p53, activated glycogen synthase kinase 3ƒÒ, phospho-tau, ubiquitin, and amyloid-ƒÒ. Real time quantitative RT-PCR analysis revealed that ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and choline acetyltransferase, and increased expression of genes encoding glial fibrillary acidic protein, microglia-specific proteins, acetylcholinesterase, tau, and amyloid precursor protein. These abnormalities were associated reduced expression of genes encoding insulin, IGF-II, insulin receptor, IGF-I receptor, and insulin receptor substrate-1, reduced ligand binding to the insulin and IGF-II receptors, and impaired learning by Morris Water Maze testing. Similar abnormalities were produced by si-RNA depletion of brain insulin and/or insulin receptor gene expression. Further studies showed that treatment with agonists of PPAR-ƒÔ or PPAR-ƒ× prevented the ic-STZ-induced Type 3 diabetes and preserved learning and memory. The results demonstrate that many of the characteristic features of AD-type neurodegeneration can be produced experimentally by selectively impairing insulin/IGF functions together with increasing oxidative stress. The findings support our hypothesis that AD represents a neuro-endocrine disorder caused by brain-specific perturbations in insulin and IGF signaling mechanisms, i.e. Type 3 diabetes. The results also suggest that early treatment with PPAR agonists may prevent or reduce the severity of AD in humans.

Dietary Lifestyle Factors and Alzheimer's Disease: Experimental Approaches and Clinical Implications
Giulio Maria Pasinetti, MD, PhD
Mount Sinai School of Medicine

Both clinical and epidemiological evidence suggest that modification of lifestyle factors such as nutrition may prove crucial to managing Alzheimer's disease. Recent experimental evidence suggests that brain cells are remarkably responsive to lifestyle modifications, including diet and physical activity. In our lab we found that experimental induced diabetes accelerates Alzheimer’s disease – type neuropathology and cognitive deterioration in Tg2576 mice that model Alzheimer’s disease (Ho et al., 2005). Conversely,