P3‐042: Pathogenesis of brain degeneration and cognitive impairment in diabetes: Implications for Alzheimer's disease

Abstract

There is an urgent need to identify biochemical factors that protect the aging brain from the progressive atrophy that leads to ever-worsening cognitive deterioration. Aging and diabetes (independent of cerebrovascular disease) are major risk factors for late-onset Alzheimer's disease (AD). Diabetes is associated with brain atrophy and dementia. Brain insulin and insulin-like growth factor (IGF) levels are reduced in both diseases. Some rats were rendered diabetic with streptozotocin, and Alzet pumps infused into their brain lateral ventricles either artificial cerebrospinal fluid (aCSF), insulin at a tiny dose that did not prevent hyperglycemia (Ins), or insulin plus IGF-I (Ins + IGF). Twelve weeks later, blood and cerebrospinal fluid were withdrawn to measure glucose. Brains were excised, weighed and processed for biochemical measurements or immunohistochemistry. Diabetic rats had significantly reduced brain wet, water and dry weights (aCSF vs. nondiabetic rats) after 12 weeks. Total DNA, protein, actin, α -tubulin, β -tubulin, glial fibrillary acidic protein (GFAP), proteolipid protein (PLP), myelin basic protein (MBP), neurofilament-light (NF-L), neurofilament medium (NF-M), and β -tubulin class III were all significantly reduced per brain. Immunostaining of GFAP, PLP, NF-M, and β -tubulin class III was reduced in the cortex and hippocampus, brain areas involved in learning and memory. (Ins + IGF) prevented the loss of all biochemical and immunohistochemical parameters in diabetic rats. (Ins) prevented loss only of brain wet, water and dry weights, as well as GFAP and PLP. However, hyperglycemia was not prevented by any treatment. IGF-I treatment prevents cognitive impairment in diabetic rats despite unabated hyperglycemia. Brain degeneration was prevented by replacing insulin and IGF in diabetic rats despite unabated hyperglycemia. Insulin and IGF are master switches regulating the levels of hundreds of brain mRNAs and proteins. IGF supports synapse formation as a likely mechanism for preventing impaired learning and memory. The age- and disease-dependent decline of insulin and IGF activities is proposed to lead to progressive loss of total brain mRNA and protein levels with abnormalities in protein processing. Prodromal brain atrophy with mild cognitive impairment may deteriorate further to brain degeneration with dementia that is diagnosed as AD.