Evidence for Compromised Insulin Signaling and Neuronal Vulnerability in Experimental Model of Sporadic Alzheimer ’s Disease

AbstractEvidence from animal studies categorizes sporadic Alzheimer ’s disease (sAD) as a metabolic syndrome with accompanying cognitive deficits. Given that glial cells act as “silent partners” to neurons by providing trophic support and defense, the present study investigated the role of glia in sAD pathology. A streptozotocin (STZ)-induced glial-neuronal co -culture model of sAD was used to study the metabolic status of the two cell types. Real time RT-PCR and Western blotting results indicated that amyloid precursor protein (APP) and β-secretase (BACE1) were highly expressed in co-cultured neurons than in monocultures. Increased amyloidogenesis was accompanied by decreased expression of mediators in insulin signaling pathway that included insulin receptor (IR), insulin receptor substrate 2 (IRS2), insulin-like growth factor 2 (IGF2), insulin-like growth factor 1 receptor (IGF1R), total-glycogen synthase kinase 3β (t-GSK3β), and phosphoryl ated-GSK3βser9 (p-GSK3 βser9), suggesting that neuronal cells are more prone to metabolic variability when cultured in the presence of glial cells. Findings from the sAD model induced by intracerebroventricular (ICV) injection of STZ revealed that increased amyloid beta (A β) load in the hippocampus was potentially responsible for the hyperphosphorylation of tau at ser396. Furthermore, impaired cognitive functions and decreased dendritic spine density and axonal thinning  in CA1 region of hippocampus were associated wi...
Source: Molecular Neurobiology - Category: Neurology Source Type: research