No abstract

No abstract

No abstract

Although extensive evidence supports the role of amyloid-β (Aβ) in Alzheimer disease (AD), the neurotoxic mechanisms underlying AD pathogenesis are not understood. On the other hand, neuronal loss is the pathological feature that best correlates with cognitive impairment. We hypothesized that cholinergic neurodegeneration may lead to Aβ deposition and tested this by inducing selective cholinergic lesions in APPswe/PS1dE9 mice with murine p75NTR saporin (mu p75-SAP). Intracerebroventricular lesions that removed ~50% of cholinergic innervation to the cortex and hippocampus were induced in animals with incipient (~3 months) and marked (~7 months of age) Aβ deposition. Cranial windows were implanted and Aβ deposition was monitored in vivo using multiphoton microscopy. Aβ deposition was increased as soon as 7 days after the lesion and this effect was maintained up to 3 months later. Postmortem studies using immunohistochemistry with an anti-Aβ antibody corroborated these findings in both cerebral cortex and hippocampus. Tau phosphorylation was also significantly increased after the lesions. Cholinergic denervation resulted in early memory impairment at 3 months of age that worsened with age (~7 months); there was a synergistic effect between cholinergic denervation and the presence of APP/PS1 transgenes. Altogether, our data suggest that cholinergic denervation may trigger Aβ deposition and synergistically contribute to cognitive impairment in AD patients.

Jiménez-Palomares M, Ramos-Rodríguez JJ, López-Acosta JF, Pacheco-Herrero M, Lechuga-Sancho AM, Perdomo G, García-Alloza M, Cózar-Castellano I. Increased A␤ production prompts the onset of glucose intolerance and insulin resistance. Am J Physiol Endocrinol Metab 302: E1373-E1380, 2012. First published March 13, 2012; doi:10.1152/ajpendo.00500.2011.-Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypothesis that AD would prompt the onset of T2D in mice. To test our hypothesis, we crossed Alzheimer APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling (db/ϩ). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. ␤-Cell mass, islet volume, and islet number were analyzed by histomorphometry. APP/ PS1 coexpression in mice with intact leptin receptor signaling did not show any metabolic perturbations in glucose metabolism or insulin sensitivity. In contrast, APP/PS1 coexpression in db/ϩ mice resulted in nonfasting hyperglycemia, hyperinsulinemia, and hypercholesterolemia without changes in body weight. Conversely, fasting blood glucose and cholesterol levels remained unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in db/ϩ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented ␤-cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant A␤ production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD. type 2 diabetes; Alzheimer's disease; ␤-amyloid peptide; APPswe/PS1dE9 mouse; db/db mouse; ␤-cell mass ALZHEIMER'S DISEASE (AD) and type 2 diabetes (T2D) are two prevalent diseases in developed countries with comparable pathological features and genetic predisposition (3, 4, 7). Several clinical and epidemiological studies have shown a relationship between AD and T2D. Patients with T2D exhibit an increased risk for developing dementia and AD (1,11,12,14,15,19). On the other hand, patients suffering AD are more vulnerable to develop T2D (10). Patients with AD show a remarkable deposition of ␤-amyloid peptide (A␤) in brain, whereas patients with T2D present islet amyloid polypeptide deposition in pancreatic ␤-cells (6). On the other hand, patients with T2D are glucose intolerant and insulin resistant, revealing decreased insulin signaling in peripheral tissues, whereas patients with AD show signs of impaired insulin signaling in the brain (16). Taken together, these observations have spurred the hypothesis that these pathological alterations may underline the mecha...

No abstract

Type 2 diabetes (T2D) is an important risk factor to suffer dementia, including Alzheimer’s disease (AD), and some neuropathological features observed in dementia could be mediated by T2D metabolic alterations. Since brain atrophy and impaired neurogenesis have been observed both T2D and AD we analyzed central nervous system (CNS) morphological alterations in the db/db mice (leptin receptor KO mice), as a model of long-term insulin resistance and T2D, and in C57Bl6 mice fed with high fat diet (HFD), as a model of diet induced insulin resistance and prediabetes. Db/db mice showed an age-dependent cortical and hippocampal atrophy, whereas in HFD mice cortex and hippocampus were preserved. We also detected increased neurogenesis and cell proliferation rates in young db/db mice when compared with control littermates. Our study shows that metabolic parameters serve as predictors of both atrophy and altered proliferation and neurogenesis in the CNS. Moreover in the cortex, atrophy, cell proliferation and neurogenesis were significantly correlated. Our data suggest that T2D may underline some of the pathological features observed in the dementia process. They also support that blood glucose control in elderly patients could help to slow down dementia evolution and maybe, improve its prognosis.

Alzheimer's disease is characterized by the presence of aggregates of amyloid beta (Ab) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric Ab. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of Ab and tau in synapse loss remain to be determined. In this study, we generated a novel transgenic mouse line, the APP/PS1/rTg21221 line, by crossing APP/PS1 mice, which develop Ab-plaques and synapse loss, with rTg21221 mice, which overexpress wild-type human tau. When compared to the APP/PS1 mice without human tau, the cross-sectional area of ThioS+ dense core plaques was increased by~50%. Along with increased plaque size, we observed an increase in plaque-associated dystrophic neurites containing misfolded tau, but there was no exacerbation of neurite curvature or local neuron loss around plaques. Array tomography analysis similarly revealed no worsening of synapse loss around plaques, and no change in the accumulation of Ab at synapses. Together, these results indicate that adding human wild-type tau exacerbates plaque pathology and neurite deformation but does not exacerbate plaque-associated synapse loss.