Abstract
Besides the continued focus on Aβ and Tau in Alzheimer's disease (AD), it is increasingly evident that other pathologic characteristics, such as vascular alterations or inflammation, are associated with AD. Whether these changes are an initial cause for the onset of AD or occur as a result of the disease in late stages is still under debate. In the present study, the impact of the high-fat diet (HFD) induced vascular risk factor hyperlipidemia on Aβ levels and clearance as well as cerebral vasculature and blood-brain barrier (BBB) integrity was examined in mice. For this purpose, human APP transgenic (APPSL) and wildtype (WT) mice were fed a HFD for 12 weeks. Plasma and tissues were subsequently investigated for Aβ distribution and concentrations of several vascular markers. Decreased plasma Aβ together with increased levels of insoluble Aβ and amyloid plaques in the brains of HFD fed APPSL mice point toward impaired Aβ clearance due to HFD. Additionally, HFD induced manifold alterations in the cerebral vasculature and BBB integrity exclusively in human APP overexpressing mice but not in wildtype mice. Therefore, HFD appears to enhance Aβ dependent vascular/BBB dysfunction in combination with an increased proportion of cerebral to plasma Aβ in APPSL mice.
Highlights
With advancing age Alzheimer’s disease (AD) is the major cause of dementia
high-fat diet (HFD) led to a profound decrease of Aβ1-40 and Aβ1-42 levels in plasma of APPSL mice at about 50 and 70%, respectively (Figure 2A)
Multiple cerebrovascular abnormalities have been identified in AD brains and clinical studies indicate that individuals with vascular risk factors, like increased plasma cholesterol, are more susceptible to AD (Puglielli et al, 2003)
Summary
With advancing age Alzheimer’s disease (AD) is the major cause of dementia. The two main histo-pathological features of AD are the extracellular deposition of amyloid β peptides (Aβ) in plaques and the formation of intracellular tangles mainly composed of hyperphosphorylated Tau protein (Selkoe, 2001). Cerebral accumulation of Aβ in LOAD patients is supposed to be a result of an imbalance between increased production and decreased clearance. Several other cerebrovascular abnormalities have been identified in AD brains such as increased microvascular density, increase of inflammatory markers, changes in vessel diameter, atherosclerotic plaques and/or cerebral amyloid angiopathy (CAA; Farkas and Luiten, 2001). It is still unclear, whether these changes are the initial cause for the onset of AD or occur as a result of the disease. In the last years, increasing evidence suggests that hypercholesterolemia and other vascular risk factors may contribute to the pathogenesis of LOAD (Skoog et al, 1999; Humpel, 2011)
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