Amyloid-β and Tau Pathology of Alzheimer's Disease Induced by Diabetes in a Rabbit Animal Model

Abstract

Alzheimer's disease (AD) is the major age-dependent disease of the brain, but what instigates late-onset AD is not yet clear. Epidemiological, animal model, and cell biology findings suggest links between AD and diabetes. Although AD pathology is accelerated by diabetes in mice engineered to accumulate human-sequence amyloid-β (Aβ) peptides, they do not adequately model non-inherited AD. We investigated AD-type pathology induced solely by diabetes in genetically unmodified rabbits which generate human-sequence Aβ peptides. After 15 weeks, alloxan-treated diabetic rabbits with expected high blood glucose showed ~5-fold increase in Aβ40/Aβ42 in cortex and hippocampus, and significantly, generated Aβ-derived assemblies found in human AD. Deposits of these putative pathogenic toxins were detected by Aβ/Aβ oligomer antibodies in brain parenchyma and surrounding vasculature, also co-localizing with markedly elevated levels of RAGE. Soluble brain extracts showed diabetes-induced buildup of Aβ oligomers on dot-blots. Phospho-tau also was clearly elevated, overlapping with βIII-tubulin along neuronal tracts. Indications of retina involvement in AD led to examination of AD-type pathology in diabetic retinas and showed Aβ accumulation in ganglion and inner nuclear cell layers using Aβ/oligomer antibodies, and RAGE again was elevated. Our study identifies emergence of AD pathology in brain and retina as a major consequence of diabetes; implicating dysfunctional insulin signaling in late-onset AD, and a potential relationship between Aβ-derived neurotoxins and retinal degeneration in aging and diabetes, as well as AD. AD-type pathology demonstrated in genetically unmodified rabbits calls attention to the considerable potential of the model for investigation of AD pathogenesis, diagnostics, and therapeutics.

TFP5, a Peptide Derived from p35, a Cdk5 Neuronal Activator, Rescues Cortical Neurons from Glucose Toxicity

“…In a recent study, AD-type CNS neuropathology was instigated in rabbit by alloxan-induced diabetes model [24], a compelling result linking AD and diabetes. Accordingly in our study, we first determined whether HG treatment induces Cdk5 hyperactivation in cortical neurons.…”

The diabetic brain and cognition

“…Central vascular disease and exacerbated pathology were seen in a mixed model of DM and AD by crossing APP/PS1 mice (AD model) with db/db mice (DM model) that show an age-dependent synergistic effect between DM and AD, including brain atrophy, senile plaques, hemorrhagic burden, and increase of microglia activation (Ramos-Rodriguez et al 2015). Insulin resistance, hyperinsulinemia, and hyperglycemia can promote the onset of AD (Rönnemaa et al 2008;de Oliveira Lanna et al 2014) by accelerating tau phosphorylation and neuritic plaque formation (Bitel et al 2012;Matsuzaki et al 2010) and, overlapping with AD pathology, aggravate the progression of neurodegeneration due to OS, mitochondrial dysfunction, neuroinflammation, etc. as a common background (Carvalho et al 2015;Kraska et al 2012;RorizFilho et al 2009;Rosales-Corral et al 2015).…”

“…A causative association between diabetes mellitus (DM) and cognitive impairment has been suggested based on clinical, epidemiological, and experimental studies (Alafuzoff et al 2009;Bitel et al 2012;Vagelatos and Eslick 2013;Carvalho et al 2015;Feinkohl et al 2015;Jellinger 2015a). In fact, recent studies demonstrate a pathophysiological link between diabetes mellitus type II (T2DM) and cognitive decline (Jellinger 2015b).…”

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

“…In AD, IlS regulates the metabolism of amyloid β plaques and tau proteins [47, 104,105]. There is a strong colocalization of NFTs with the phosphorylated (and inactivated) IRS-1/2 receptors [106] directly associating diabetes pathology with exasperated AD.…”