Comorbid Rat Model of Ischemia and β‐Amyloid Toxicity: Striatal and Cortical Degeneration

Abstract

Levels of cerebral amyloid, presumably β-amyloid (Abeta), toxicity and the incidence of cortical and subcortical ischemia increases with age. However, little is known about the severe pathological condition and dementia that occur as a result of the comorbid occurrence of this vascular risk factor and Abeta toxicity. Clinical studies have indicated that small ischemic lesions in the striatum are particularly important in generating dementia in combination with minor amyloid lesions. These cognitive deficits are highly likely to be caused by changes in the cortex. In this study, we examined the viability and morphological changes in microglial and neuronal cells, gap junction proteins (connexin43) and neuritic/axonal retraction (Fer Kinase) in the striatum and cerebral cortex using a comorbid rat model of striatal injections of endothelin-1 (ET1) and Abeta toxicity. The results demonstrated ventricular enlargement, striatal atrophy, substantial increases in β-amyloid, ramified microglia and increases in neuritic retraction in the combined models of stroke and Abeta toxicity. Changes in connexin43 occurred equally in both groups of Abeta-treated rats, with and without focal ischemia. Although previous behavioral tests demonstrated impairment in memory and learning, the visual discrimination radial maze task did not show significant difference, suggesting the cognitive impairment in these models is not related to damage to the dorsolateral striatum. These results suggest an insight into the relationship between cortical/striatal atrophy, pathology and functional impairment.

Quercetin promotes learning and memory performance concomitantly with neural stem/progenitor cell proliferation and neurogenesis in the adult rat dentate gyrus

“…A rat model of AD was established by direct Aβ (1-42; Sigma) injection. Briefly, the rats in groups (AD + NS and AD + Q) were anesthetized intraperitoneally with chloral hydrate solution and placed into a stereotaxic apparatus (Stoelting, USA) (Amtul et al, 2015;Kim et al, 2014). The stereotaxic apparatus was coordinated to conduct microinjection (AP: -0.8, ML: ± 1.4 and DV: −4 mm) below dura and standardized using by a stereotaxic atlas of Paxinos and Watson.…”

Targeted Antioxidant, Catalase–SKL, Reduces Beta‐Amyloid Toxicity in the Rat Brain

“…Therefore, the aim of the present study was to evaluate whether the targeted antioxidant CAT-SKL is able to reduce the toxicity induced by Ab [25][26][27][28][29][30][31][32][33][34][35] administration in the mature rat brain. Previous work has demonstrated the toxicity induced by intracerebroventricular (icv) administration of Ab [25][26][27][28][29][30][31][32][33][34][35] in the rodent brain, with pathological changes including increased activation of inflammatory cells, loss of hippocampal and cholinergic neurons, and cognitive deficits being realized (2,3,5,22,(40)(41)(42). Results from this study demonstrate the ability of CAT-SKL to reduce Ab induced microglia and astrocyte activation, enhance cholinergic neuronal survival and attenuate long-term reference memory deficits in rats.…”

Selective Astrocytic Endothelin-1 Overexpression Contributes to Dementia Associated with Ischemic Stroke by Exaggerating Astrocyte-Derived Amyloid Secretion

“…25 Recently, the link between ET-1, Aβ, and cognitive deficit has been emerged. 18,26 These findings suggest that astrocytic ET-1 may have a critical role in the pathogenesis of I/R and AD.…”

“…Intracerebroventricular 7 or hippocampal 17 administration of Aβ to those mice was found to exacerbate the AD-like cognitive deficit. The striatal injection of ET-1 causes significant elevation of amyloid precursor protein fragments including Aβ deposition, 18 suggesting that upregulation of ET-1 during ischemic stroke may responsible for the Aβ production and accumulation, which is neurotoxic to the brain cells and results in impairment of the neurovascular unit, such as BBB breakdown. In addition, overexpression of ET-1 in the endothelial cells exacerbates anxiety-like behavior and spatial reference learning and memory impairment after a short-term ischemia with 7-day reperfusion 16 suggesting the importance of endothelial ET-1 in Aβ and dementia.…”