Human apolipoprotein E4 alters the amyloid-beta 40 : 42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model
ABSTRACT Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-beta (Abeta) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA). CAA is a common cause of brain hemorrhage and is found in most patients with AD. As in AD, the epsilon4 allele of the apolipoprotein E (apoE) gene (APOE) is a risk factor for CAA. To determine the effect of human apoE on CAA in vivo, we bred human APOE3 and APOE4 "knock-in" mice to a transgenic mouse model (Tg2576) that develops amyloid plaques as well as CAA. The expression of both human apoE isoforms resulted in a delay in Abeta deposition of several months relative to murine apoE. Tg2576 mice expressing the more fibrillogenic murine apoE develop parenchymal amyloid plaques and CAA by 9 months of age. At 15 months of age, the expression of human apoE4 led to substantial CAA with very few parenchymal plaques, whereas the expression of human apoE3 resulted in almost no CAA or parenchymal plaques. Additionally, young apoE4-expressing mice had an elevated ratio of Abeta 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of Abeta species within different brain compartments. These findings demonstrate that, once Abeta fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of Abeta 40:42 may favor the formation of CAA versus parenchymal plaques.
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ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia, which is characterized by the neuropathological accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs). Clinically, patients will endure a gradual erosion of memory and other higher order cognitive functions. Whilst the underlying etiology of the disease remains to be definitively identified, a body of work has developed over the last two decades demonstrating that AD plasma/serum and brain are characterized by a dyshomeostasis in a number of metal ions. Furthermore, these metals (such as zinc, copper and iron) play roles in the regulation of the levels of AD-related proteins, including the amyloid precursor protein (APP) and tau. It is becoming apparent that metals also interact with other proteins, including apolipoprotein E (ApoE). The Apolipoprotein E gene (APOE) is critically associated with AD, with APOE4 representing the strongest genetic risk factor for the development of late-onset AD. In this review we will summarize the evidence supporting a role for metals in the function of ApoE and its consequent role in the pathogenesis of AD.Frontiers in Aging Neuroscience 06/2014; 6:121. DOI:10.3389/fnagi.2014.00121 · 2.84 Impact Factor
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ABSTRACT: Cerebrovascular dysfunction significantly contributes to the clinical presentation and pathoetiology of Alzheimer's disease (AD). Deposition and aggregation of β-amyloid (Aβ) within vascular smooth muscle cells leads to inflammation, oxidative stress, impaired vasorelaxation, and disruption of blood-brain barrier integrity. Midlife vascular risk factors, such as hypertension, cardiovascular disease, diabetes, and dyslipidemia, increase the relative risk for AD. These comorbidities are all characterized by low and/or dysfunctional high-density lipoproteins (HDL), which itself is a risk factor for AD. HDL performs a wide variety of critical functions in the periphery and CNS. In addition to lipid transport, HDL regulates vascular health via mediating vasorelaxation, inflammation, and oxidative stress and promotes endothelial cell survival and integrity. Here, we summarize clinical and preclinical data examining the involvement of HDL, originating from the circulation and from within the CNS, on AD and hypothesize potential synergistic actions between the two lipoprotein pools.Cell metabolism 02/2014; DOI:10.1016/j.cmet.2014.01.003 · 16.75 Impact Factor
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ABSTRACT: Aquaporin-4 (AQP4) is the predominant water channel in brain and is selectively expressed in astrocytes. Astrocytic endfoot membranes exhibit tenfold higher densities of AQP4 than non-endfoot membranes, making AQP4 an excellent marker of astrocyte polarization. Loss of astrocyte polarization is known to compromise astrocytic function and to be associated with impaired water and K+ homeostasis. Here we investigate by a combination of light and electron microscopic immunocytochemistry whether amyloid deposition is associated with a loss of astrocyte polarization, using AQP4 as a marker. We used the tg-ArcSwe mouse model of Alzheimer's disease, as this model displays perivascular plaques as well as plaques confined to the neuropil. 3D reconstructions were done to establish the spatial relation between plaques and astrocytic endfeet, the latter known to contain the perivascular pool of AQP4. Changes in AQP4 expression emerge just after the appearance of the first plaques. Typically, there is a loss of AQP4 from endfoot membranes at sites of perivascular amyloid deposits, combined with an upregulation of AQP4 in the neuropil surrounding plaques. By electron microscopy it could be verified that the upregulation reflects an increased concentration of AQP4 in those delicate astrocytic processes that abound in synaptic regions. Thus, astrocytes exhibit a redistribution of AQP4 from endfoot membranes to non-endfoot membrane domains. The present data suggest that the development of amyloid deposits is associated with a loss of astrocyte polarization. The possible perturbation of water and K+ homeostasis could contribute to cognitive decline and seizure propensity in patients with Alzheimer's disease.Journal of Alzheimer's disease: JAD 09/2011; 27(4):711-22. DOI:10.3233/JAD-2011-110725 · 3.61 Impact Factor