Modeling sporadic alzheimer's disease: the insulin resistant brain state generates multiple long-term morphobiological abnormalities inclusive hyperphosphorylated tau protein and amyloid-beta. A Synthesis

Nosologically, Alzheimer's disease (AD) is not a single disorder. Missense gene mutations involved in increased formation of the amyloid-beta protein precursor derivatives amyloid-beta (Abeta)_{1-40} and Abeta_{1-42/43} lead to autosomal dominant familial AD, found in the minority of AD cases. However, millions of subjects suffer from sporadic AD (sAD) of late onset, for which no convincing evidence suggests Abeta as the primary disease-generating compound. Environmental factors operating during pregnancy and postnatally may affect susceptibility genes and stress factors (e.g., cortisol), consequently affecting brain development both structurally and functionally, causing disorders becoming manifest late in life. With aging, a desynchronization of biological systems may result, increasing further brain entropy/declining criticality. In sAD, this desynchronization may involve stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates causing an insulin resistant brain state with decreased glucose/energy metabolism. This further leads to a derangement of ATP-dependent cellular and molecular work, of the cell function in general, as well as derangements in the endoplasmic reticulum/Golgi apparatus, axon, synapses, and membranes, in particular. A self-propagating process is thus generated, including the increased formation of hyperphosphorylated tau-protein and Abeta as abnormal terminal events in sAD rather than causing the disorder, as elaborated in the review

Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats: A Role for Glycogen Synthase Kinase-3β

OBJECTIVE—There is evidence that insulin reduces brain injury evoked by ischemia/reperfusion (I/R). However, the molecular mechanisms underlying the protective effects of insulin remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3β (GSK-3β). Here, we investigate the role of GSK-3β inhibition on I/R-induced cerebral injury in a rat model of insulinopenic diabetes

The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner

Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O6-methyldeoxyguanosine lesions, O6-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O6-mG DNA methyltransferase (MGMT) showed elevated O6-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease

Translational models for vascular cognitive impairment: a review including larger species.

BACKGROUND: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. METHODS: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). CONCLUSIONS: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required

Modeling Sporadic Alzheimer's Disease: The Insulin Resistant Brain State Generates Multiple Long-Term Morphobiological Abnormalities Including Hyperphosphorylated Tau Protein and Amyloid-β

Nosologically, Alzheimer's disease (AD) is not a single disorder. Missense gene mutations involved in increased formation of the amyloid-beta protein precursor derivatives amyloid-beta (Abeta)_{1-40} and Abeta_{1-42/43} lead to autosomal dominant familial AD, found in the minority of AD cases. However, millions of subjects suffer from sporadic AD (sAD) of late onset, for which no convincing evidence suggests Abeta as the primary disease-generating compound. Environmental factors operating during pregnancy and postnatally may affect susceptibility genes and stress factors (e.g., cortisol), consequently affecting brain development both structurally and functionally, causing disorders becoming manifest late in life. With aging, a desynchronization of biological systems may result, increasing further brain entropy/declining criticality. In sAD, this desynchronization may involve stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates causing an insulin resistant brain state with decreased glucose/energy metabolism. This further leads to a derangement of ATP-dependent cellular and molecular work, of the cell function in general, as well as derangements in the endoplasmic reticulum/Golgi apparatus, axon, synapses, and membranes, in particular. A self-propagating process is thus generated, including the increased formation of hyperphosphorylated tau-protein and Abeta as abnormal terminal events in sAD rather than causing the disorder, as elaborated in the review

Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer's disease

Sporadic Alzheimer disease (sAD) is associated with impairment of insulin receptor (IR) signalling in the brain. Rats used to model sAD develop insulin-resistant brain state following intracerebroventricular treatment with a betacytotoxic drug streptozotocin (STZ-icv). Brain IR signalling has been explored usually at only one time point in periods ≤3 months after the STZ-icv administration. We have investigated insulin signalling in the rat hippocampus at five time points in periods ≤9 months after STZ-icv treatment. Male Wistar rats were given vehicle (control)- or STZ (3 mg/kg)-icv injection and killed 0.5, 1, 3, 6 and 9 months afterwards. Insulin-1 (Ins-1), IR, phospho- and total (p/t)-glycogen synthase kinase 3-β (GSK-3β), p/t-tau and insulin degrading enzyme (IDE) mRNA and/or protein were measured. Acute upregulation of tau and IR mRNA (p < 0.05) was followed by a pronounced downregulation of Ins-1, IR and IDE mRNA (p < 0.05) in the course of time. Acute decrement in p/t-tau and p/t-GSK-3β ratios (p < 0.05) was followed by increment in both ratios (3-6 months, p < 0.05) after which p/t-tau ratio demonstrated a steep rise and p/t-GSK-3β ratio a steep fall up to 9 months (p < 0.05). Acute decline in IDE and IR expression (p < 0.05) was followed by a slow progression of the former and a slow recovery of the latter in 3-9 months. Results indicate a biphasic pattern in time dependency of onset and progression of changes in brain insulin signalling of STZ-icv model (partly reversible acute toxicity and chronic AD-like changes) which should be considered when using this model as a tool in translational sAD research