Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice

Abstract

A number of studies suggest an association between Alzheimer's disease (AD) and diabetes: AD patients show impaired insulin function, whereas cognitive deficits and increased risk of developing AD occur in diabetic patients. The reasons for the increased risk are not known. Recent studies of disturbances in the insulin-signaling pathway have revealed new perspectives on the links between AD and Type 1 diabetes with a particular focus on glycogen synthase-kinase-3 (GSK3). We have therefore characterized a mouse model of combined insulin-deficient diabetes and AD and find that diabetes exaggerated defects in the brain of APP transgenic mice. Mice with combined APP overexpression and diabetes showed a decreased insulin receptor activity and an increased GSK3β activity. Concomitantly, tau phosphorylation and number of Aβ plaques, the two pathologic hallmarks of AD, were increased in the brain of diabetic-APP transgenic mice. Our results indicate that the pathologic features of AD are exaggerated in the brain of APP transgenic mice that have concurrent insulin-deficient diabetes, and underscore a possible mechanism of brain dysfunction common to AD and diabetes.

Pen-2 overexpression induces Aβ-42 production, memory defect, motor activity enhancement and feeding behavior dysfunction in NSE/Pen-2 transgenic mice

“…In a study using APP23-ob/ob double mutant mice, the onset of diabetes exacerbated AD-like cognitive dysfunction, without Aβ peptide deposition (39). Also, mice overexpressing APP and displaying type 1 diabetes showed a decrease of insulin receptor activity, increase of GSK3β activity, increase of Tau phosphorylation and Aβ plaque number (40). In the present study, the increase of pathological features of diabetes and obesity were detected in the NSE/hPen-2 Tg mice compared with non-Tg mice.…”

Tauopathy and cognitive impairment in experimental diabetes mellitus

“…Jolivalt демонстрируют нарушение сигнального пути инсулина и активности фосфорилирования тау-белка после 9 недель стрепто-зотоцин-индуцированного диабета в мозге мышей [35]. Таким образом, дефекты сигнальных путей инсулина имеют основополагающее значение для развития когни-тивных нарушений, которые могут возникать либо от де-фицита инсулина (СД1), либо вследствие резистентности к инсулину (СД2), вызывая аномальную активацию GSK-3 [36][37][38][39][40]. Данные влияния различных тау-фосфа-таз на моделях с СД на развитие когнитивных наруше-ний мало изучены по сравнению с GSK-3 .…”

Dogs with Cognitive Dysfunction Syndrome: A Natural Model of Alzheimer’s Disease

“…Other models with AD-like pathology are apolipoprotein E (ApoE) or Tau transgenic mice, and also mice in which other genes have been modified. In more sophisticated approaches, important information has been gained from crossing PDAPP and ApoE models and with mice lacking or over-expressing genes for beta-secretase, alpha-secretase, or the insulin-degrading enzyme [9,10].…”

“…Other models with AD-like pathology are apolipoprotein E (ApoE) or Tau transgenic mice, and also mice in which other genes have been modified. In more sophisticated approaches, important information has been gained from crossing PDAPP and ApoE models and with mice lacking or over-expressing genes for beta-secretase, alpha-secretase, or the insulin-degrading enzyme [9,10].All these models have provided valuable information on AD pathology and on the possibility of developing new treatments such as secretase inhibitor therapy or immunotherapy.However, transgenic models are plagued with limitations, especially in terms of their ability to fully represent a correspondence between mutations and disease. For example, in mouse models, mutations in amyloid precursor protein (APP) and presenilin frequently trigger only Aβ plaques, whereas in humans these mutations lead to AD with plaques, tangles, and severe brain atrophy.…”