Human apolipoprotein E4 alters the amyloid-β 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model

Duke University, Durham, North Carolina, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2005; 25(11):2803-10. DOI: 10.1523/JNEUROSCI.5170-04.2005
Source: PubMed


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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    • "Aβ deposition detected by Pittsburgh Compound B positron emission tomography (PIB- PET) follows a strong APOE allele-dependent pattern (E4 > E3 > E2) (Kok et al., 2009; Morris et al., 2010; Castellano et al., 2011). An ApoE isoform-specific effect on the amount of Aβ accumulation as well as in the number of amyloid plaques was also found in amyloid precursor protein (APP) transgenic mice expressing different human ApoE isoforms (E4 > E3 > E2; Fagan et al., 2000, 2002; Fryer et al., 2005b). The mechanisms underlying isoform-specific influences on Aβ aggregation and accumulation in the brains are not fully understood, but it's likely due to their different abilities to clear Aβ (Wildsmith et al., 2013). "
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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 · 4.00 Impact Factor
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    • "One hypothesis to account for these observations is that apoE4 enhances Ab deposition within the cerebrovascular walls, while apoE2 increases the risk for hemorrhage of amyloid-laden cerebral blood vessels (McCarron and Nicoll, 2000). Animal model studies show that CAA is increased in apoE4-expressing transgenic AD mouse models (Fryer et al., 2005). Mechanistically, apoE4 retards Ab clearance across the BBB and via the perivascular drainage pathway (Castellano et al., 2011; Deane et al., 2008; Hawkes et al., 2012; Verghese et al., 2013), potentially driving CAA formation and BBB breakdown. "
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    Cell metabolism 02/2014; 19(4). DOI:10.1016/j.cmet.2014.01.003 · 17.57 Impact Factor
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    • "This could be supported through considering the lower Aβ 40/42 ratios recorded in the present study in autistic patients compared to control subjects. It is well known that clearance and transport from brain to blood is facilitated by an increased Aβ 40/42 ratio present at young ages [44]. Moreover, young mouse model harboring a mutation favoring generation of Aβ 1-42 over Aβ 1-40 had a low Aβ 40/42 ratio, was shifted to plaque deposition [45]. "
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    ABSTRACT: We examined whether plasma concentrations of amyloid beta (Aβ) as protein derivatives play a central role in the etiology of autistic features. Concentrations of human Aβ (1-42), Aβ (1-40), and Aβ (40/42) in the plasma of 52 autistic children (aged 3-16 years) and 36 age-matched control subjects were determined by using the ELISA technique and were compared. Compared to control subjects, autistic children exhibited significantly lower concentrations of both Aβ (1-40) and Aβ (1-42) and lower Aβ (40/42) concentration ratio. Receiver operating characteristics curve (ROC) analysis showed that these measurements of Aβ peptides showed high specificity and sensitivity in distinguishing autistic children from control subjects. Lower concentrations of Aβ (1-42) and Aβ (1-40) were attributed to loss of Aβ equilibrium between the brain and blood, an imbalance that may lead to failure to draw Aβ from the brain and/or impairment of β- and γ- secretase's concentration or kinetics as enzymes involving in Aβ production.
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