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.

Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer’s Disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. In parallel, AD patients have a higher than normal tendency to develop type 2 diabetes or impaired fasting glucose. Tau is the major component of neurofibrillary tangles (NFT), one of the hallmarks of AD pathology. The current study examined the effect of hyperglycemia on tau modification. Glucose treatment of rat embryonic cortical neurons results in concentration-dependent apoptosis and caspase-3 activation. These changes are well correlated with glucose time- and concentration-dependent tau cleavage. Aβ treatment induces tau cleavage and when added together with glucose there is an additive effect on caspase activation, apoptosis and tau cleavage. Tau cleavage is partially blocked by the caspase inhibitor, ZVAD. Cleaved tau displays a punctate staining along the neurites and colocalizes with cleaved caspase-3 in the cytoplasm. Both type 1 and type 2 diabetic mice display increased tau phosphorylation in the brain. In agreement with the effects of glucose on tau modifications in vitro, there is increased tau cleavage in the brains of ob/ob mice; however, tau cleavage is not observed in type 1 diabetic mouse brains. Our study demonstrates that hyperglycemia is one of major factors that induce tau modification in both in vitro and in vivo models of diabetes. We speculate that tau cleavage in diabetic conditions (especially in type 2 diabetes) may be a key link for the increased incidence of AD in diabetic patients.

Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle, low-dose (375 mg/kg) dimethylthiourea, high-dose (750 nig/kg) dimethylthiourea, low-dose (0.5 mg/kg) MK-801, high-dose (2.0 mg/kg) MK-801, or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia, brain water content was determined. In eight vehicle-treated controls, mean±SEM water content of tissue in the center of the ischemic zone was 83.29±0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example, 50.2% (p<0.001) in the high-dose dimethylthiourea group, 53.7% (p<0.001) in the low-dose MK-801 group, and 66.4% (/?<0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone. These results indicate that pretreatment with either dimethylthiourea or MK-801 can reduce brain edema during the early stages of cerebral ischemia and further suggest that excitatory amino acids and oxygen free radicals may damage the brain by a common pathway. Supported by a grant-in-aid from the American Heart Association of Michigan.Address for correspondence: A. Lorris Betz, MD, PhD, D3227 Medical Professional Building, University of Michigan, Ann Arbor, MI 48109-0718.Received December 28, 1990; accepted March 18, 1991. have shown that excitatory amino acid receptor antagonists have a protective effect on brain following cerebral ischemia. -28One putative source of oxygen free radicals during cerebral ischemia is the arachidonic acid cascade. 29 " 31 Since the activation of excitatory neurotransmitter receptors leads to the release of arachidonic acid, 32 excitatory amino acids could theoretically cause the generation of oxygen free radicals by this mechanism during cerebral ischemia. In support of this hypothesis, oxygen free radical quenchers or lipid peroxidation inhibitors were recently shown to reduce excitatory amino acid-induced neuronal injury in vitro. 33- 34 Other recent reports suggest that oxygen free radicals can themselves cause excitatory amino acid release. PellegriniGiampietro et al 35 reported that oxygen free radicals generated from xanthine-xanthine oxidase stimulated the release of excitatory amino acids from rat hippocampal slices. Furthermore, in an in vitro ischemic model, oxygen free radical quenchers prevented the release of excitatory amino acids. jury mechanisms dur...