Hypercholesterolemia accelerates amyloid β-induced cognitive deficits

Abstract

Hypercholesterolemia is a known risk factor for Alzheimer's disease (AD). In the present study, we investigated whether diet-induced hypercholesterolemia affects AD-like pathologies such as amyloid β-peptide (Aβ) deposition, tau pathology, inflammation and cognitive impairment, using an Aβ25-35-injected AD-like pathological mouse model. Hypercholesterolemia was induced by providing apolipoprotein E knock out (Apo E KO) mice with a high-fat diet for 4 weeks prior to Aβ25-35 injection and for 4 weeks following Aβ25-35 injection, for a total of 8 weeks of treatment. Our data showed that intracerebroventricular injection of C57BL/6J mice with Aβ25-35 resulted in increased immunoreactivity of Aβ and phosphorylated-tau (p-tau), which was accompanied by enhanced microglial CD11b-like immunoreactivity in the brain. Moreover, hypercholesterolemia slightly increased Aβ and p-tau levels and microglial activation in the vehicle group, while further increasing the Aβ and p-tau levels and microglial activation in Aβ25-35-injected mice. Consistent with the neuropathological analysis, hypercholesterolemia resulted in significant spatial learning and memory deficits in Aβ25-35-injected mice as revealed by water maze testing. Collectively, these findings demonstrated that hypercholesterolemia accelerated Aβ accumulation and tau pathology, which was accompanied by microglial activation and subsequent aggravation of memory impairment induced by Aβ25-35. Thus, we suggest that the modulation of cholesterol can be used to reduce the risk of developing AD.

27-Hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain

“…Dysregulation of cholesterol homeostasis is a well-14 established risk factor for Alzheimer's disease (AD) 15 pathophysiology and has been shown to affect the 16 progression of cognitive impairment and neural 17 degeneration (Jansen et al, 2012;Park et al, 2013). 18 Abnormal cholesterol metabolism states in the brain are 19 likely to include aberrant neuronal function, interrupted 20 cell-cell interactions, myelin breakdown, and neuronal 21 loss (Bjorkhem, 2006).…”

Framingham risk score can predict cognitive decline progression in Alzheimer's disease

“…Cholesterol is a well-recognized factor for promoting amyloid-peptide deposition and amyloid precursor protein processing, 2 fundamental elements involved in AD pathogenesis (Paternoster et al, 2010). Furthermore, hypercholesterolemia is strictly related to intracranial atherosclerosis, a recognized contributing factor for vascular impairment in AD (Park et al, 2013;Silvestrini et al, 2012).…”

Elevated LDL-C combined with hypertension worsens subclinical vascular impairment and cognitive function

“…Several hypotheses have been previously proposed to provide plausible explanation for the pathomechanism of neuropsychological deterioration in the setting of hypertension; structural vascular changes leading to extracellular edema, disruption of the blood-brain barrier, chronic cortical deafferentation resulting in vessel obstruction leading to ischemia, 50 insufficient cerebral blood flow, 51,52 disturbed cerebral metabolism, autoregulation or neurochemistry, enhanced cardiovascular and neuroendocrine reactivity, 52,53 anxiety, 54 and so forth. Likewise, the pathophysiology of hyperlipidemia-associated cognitive decline has also been thoroughly studied (b-amyloid generation, t-hyperphosphorylation, inflammation in the brain, 55,56 etc. ), but the exact links between cognitive impairment and these two important cerebrovascular and cardiovascular risk factors are yet to be clarified.…”