Increased Tau Phosphorylation and Cleavage in Mouse Models of Type 1 and Type 2 Diabetes

Abstract

As the population of the United States ages, the incidence of age-related neurodegenerative and systemic diseases including Alzheimer's disease (AD) and diabetes is increasing rapidly. Multiple studies report that patients with diabetes have a 50-75% increased risk of developing AD compared with age- and gender-matched patients without diabetes. Abnormally phosphorylated tau is a major building block of neurofibrillary tangles, a classic neuropathological characteristic of AD. In addition, proteolytic tau cleavage promotes AD progression due to cleaved tau serving as a nucleation center for the pathological assembly of tau filaments. The current study examines tau modification in type 1 (streptozotocin-injected) and type 2 (db/db) mouse models of diabetes. Tau phosphorylation is increased in the cortex and hippocampus of db/db mice compared with db+ control mouse brain. Interestingly, there is an age-dependent increase in tau cleavage that is not observed in age-matched control db+ animals. Streptozotocin injection also increased tau phosphorylation; however, the increase was less significant compared with the type 2 mouse model, and more importantly, no tau cleavage was detected. Our results suggest tau modification caused by insulin dysfunction and hyperglycemia may contribute to the increased incidence of AD in diabetes. We hypothesize that type 1 and type 2 diabetes may contribute to AD through different mechanisms; in type 2 diabetes, hyperglycemia-mediated tau cleavage may be the key feature, whereas insulin deficiency may be the major contributing factor in type 1 diabetes.

Changes in Cyclooxygenase-2 Immunoreactivity in the Hippocampus in a Model of Streptozotocin-Induced Type 1 Diabetic Rats

“…3). DISCUSSION Diabetic brain shows cognitive deficits and increased risk of developing dementia, especially the incidence of Alzheimer's disease [18]. In a previous study, the MRI differences in brain lesions between the two type diabetes were compared and more prominent cognitive disturbances were found in type 2 DM [3].…”

“…Its toxicity is induced by DNA alkylating activity of its methylnitrosourea moiety, poly-ADP-ribose polymerase overstimulation, and cellular energy depletion [20]. In many studies including ours, STZ-induced animal models are used for studying the effects of type 1 diabetes mellitus [5,18,32].…”

Cortical Neurons Develop Insulin Resistance and Blunted Akt Signaling: A Potential Mechanism Contributing to Enhanced Ischemic Injury in Diabetes

“…Lysates were collected, briefly sonicated, and centrifuged at 13,000 rpm for 15 min at 4°C. Western immunoblotting was performed as described previously (33). TBS with 0.01% Tween-20 and 5% fat-free milk was used for blocking and antibody dilution.…”

Neuroprotective Effect of Epalrestat on Memory Impairment in Streptozotocin-Induced Type-2 Diabetic Rats Using Different Behavioral Models.

“…This finding indicated memory retention in treated rats. In several studies, these cognitive deficits in diabetes were correlated for probable mechanisms such as hyperglycemiainduced end-organ neuronal damage, dyslipidemia, amyloidopathy, and tauopathy [31,32].…”