Cerebral amyloid angiopathy: Pathogenetic mechanisms and link to dense amyloid plaques

Neurodegenerative Brain Diseases Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
Genes Brain and Behavior (Impact Factor: 3.66). 03/2008; 7 Suppl 1(s1):67-82. DOI: 10.1111/j.1601-183X.2007.00380.x
Source: PubMed


Cerebral amyloid angiopathy (CAA) of the amyloid-β (Aβ) type is the most common form of sporadic CAA and is now also accepted as an early and integral part of Alzheimer's disease (AD) pathogenesis. Cerebral amyloid angiopathy is a risk factor for haemorrhagic stroke and is believed to independently contribute to dementia. Rare forms of hereditary cerebral amyloidosis caused by mutations within the Aβ domain of amyloid precursor protein (APP) have been identified, where mutant Aβ preferably deposits in vessels because of a decreased fibrillogenic potential and/or increased vasotopicity. A review of factors involved in CAA caused by wild-type Aβ suggests that increased Aβ levels in brain without an increased Aβ42/Aβ40 ratio is one of the most important prerequisites for vascular amyloidosis. This is exemplified by CAA observed in APP duplication and Down's syndrome patients, neprilysin polymorphism patients and knockout mice and Swedish APP (KM670/671NL) mice. Select presenilin mutations also lead to a prominent CAA, and importantly, presenilin mutations are shown to have varied effects on the production of Aβ40, the predominant amyloid found in CAA. Conversely, APP mutations such as Austrian APP (T714I) drastically decrease Aβ40 production and are deficient in CAA. Apolipoprotein E-ε4 is also shown to be a risk factor for CAA, and this might be because of its specific role in the aggregation of Aβ40. Recent data also suggest that dense-core senile plaques in humans and dense plaques in transgenic mice, composed predominantly of Aβ40, associate with vessels. This review highlights some of these aspects of genetics and biochemistry of CAA and pathological descriptions linked to a prominent CAA and/or dense plaques in humans and relevant mouse models and discusses how this knowledge has led to a better understanding of the processes involved in vascular amyloidosis, and in causing dementia, and thus has important therapeutic implications.

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    • "Such data is essential in order to develop a mechanistic understanding as to if, and how, obesity modulates neurodegenerative processes involved in diseases such as AD. Cerebral amyloid angiopathy (CAA) occurs in nearly all cases of Alzheimer's disease (AD), Down's syndrome, and is the second leading cause of intracerebral hemorrhage [24] [25] [26] [27] [28]. CAA is caused by the accumulation of amyloid within the cerebrovasculature, and is associated with numerous alterations relevant to AD and other neurodegenerative conditions including neuroinflammation, oxidative stress, and gliosis. "
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    ABSTRACT: Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.
    Biochimica et Biophysica Acta 01/2013; 1832(9). DOI:10.1016/j.bbadis.2013.01.002 · 4.66 Impact Factor
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    • "The specific contributions of APP to the complications of obesity remain largely undefined. Furthermore, the impact of APP mutations associated with AD and cerebral amyloid angiopathy (CAA) [12]–[14] have not been well established in adipose tissue. Understanding the potential for APP, and mutant APP expression, to modulate specific aspects of adipose-associated endocrine and metabolic function may provide novel insight as to how peripheral APP expression contributes to the global physiological changes, and potentially the modulation of brain homeostasis. "
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    ABSTRACT: Mutations in amyloid precursor protein (APP) have been most intensely studied in brain tissue for their link to Alzheimer's disease (AD) pathology. However, APP is highly expressed in a variety of tissues including adipose tissue, where APP is also known to exhibit increased expression in response to obesity. In our current study, we analyzed the effects of mutant APP (E693Q, D694N, K670N/M671L) expression toward multiple aspects of adipose tissue homeostasis. These data reveal significant hypoleptinemia, decreased adiposity, and reduced adipocyte size in response to mutant APP, and this was fully reversed upon high fat diet administration. Additionally, mutant APP was observed to significantly exacerbate insulin resistance, triglyceride elevations, and macrophage infiltration of adipose tissue in response to a high fat diet. Taken together, these data have significant implications for linking mutant APP expression to adipose tissue dysfunction and global changes in endocrine and metabolic function under both obesogenic and non-obesogenic conditions.
    PLoS ONE 08/2012; 7(8):e43193. DOI:10.1371/journal.pone.0043193 · 3.23 Impact Factor
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    • "The neural pathology of AD includes senile plaques, neurofibrillary tangles, and loss of neurons. In addition, there is a significant vascular pathology in AD characterized by amyloid deposits in cerebral vessel walls (cerebral amyloid angiopathy), as well as structural abnormalities in the microvasculature (Revesz et al., 2003; Bailey et al., 2004; Kumar-Singh, 2008; Storkebaum et al., 2011). The amyloid precursor protein (APP) is known to be the source of the hydrophobic peptide amyloid b (Ab) that is a major component of amyloid deposits in the brains of AD patients (Kang et al., 1987; Newman et al., 2007; Additional Supporting Information may be found in the online version of this article. "
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    ABSTRACT: The single spanning transmembrane amyloid precursor protein (APP) and its proteolytic product, amyloid-beta (Ab) peptide, have been intensely studied due to their role in the pathogenesis of Alzheimer's disease. However, the biological role of the secreted ectodomain of APP, which is also generated by proteolytic cleavage, is less well understood. Here, we report Tol2 red fluorescent protein (RFP) transposon gene trap integrations in the zebrafish amyloid precursor protein a (appa) and amyloid precursor-like protein 2 (aplp2) genes. The transposon integrations are predicted to disrupt the appa and aplp2 genes to primarily produce secreted ectodomains of the corresponding proteins that are fused to RFP. Our results indicate the Appa-RFP and Aplp2 fusion proteins are likely secreted from the central nervous system and accumulate in the embryonic veins independent of blood flow. The zebrafish appa and aplp2 transposon insertion alleles will be useful for investigating the biological role of the secreted form of APP.
    Developmental Dynamics 02/2012; 241(2):415-25. DOI:10.1002/dvdy.23725 · 2.38 Impact Factor
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