Alzheimer’s-Related Peptide Amyloid-β Plays a Conserved Role in Angiogenesis

Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America.
PLoS ONE (Impact Factor: 3.23). 07/2012; 7(7):e39598. DOI: 10.1371/journal.pone.0039598
Source: PubMed


Alzheimer's disease research has been at an impasse in recent years with lingering questions about the involvement of Amyloid-β (Aβ). Early versions of the amyloid hypothesis considered Aβ something of an undesirable byproduct of APP processing that wreaks havoc on the human neocortex, yet evolutionary conservation--over three hundred million years--indicates this peptide plays an important biological role in survival and reproductive fitness. Here we describe how Aβ regulates blood vessel branching in tissues as varied as human umbilical vein and zebrafish hindbrain. High physiological concentrations of Aβ monomer induced angiogenesis by a conserved mechanism that blocks γ-secretase processing of a Notch intermediate, NEXT, and reduces the expression of downstream Notch target genes. Our findings allude to an integration of signaling pathways that utilize γ-secretase activity, which may have significant implications for our understanding of Alzheimer's pathogenesis vis-à-vis vascular changes that set the stage for ensuing neurodegeneration.

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Available from: Harpreet Sidhu
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    • "In addition to the significant genetic similarity to humans, homologue genes encoding several proteins related to AD were identified [20] [21] [42], including the amyloid precursor protein (APP) with 80% of conservation [20]. This is the first report of Aβ brain injection in zebrafish, in parallel to Cunvong et al. [28] that injected the same peptide in the retina and Cameron et al. [43] that exposed embryos to amyloid-β 1–42 in the water. The original brain ventricle microinjection protocol from Gutzman and Sive [27] for 24 hpf zebrafish embryos was adapted and proved feasible in large scale, requiring a relatively accessible setup in which trained experimenters injected one embryo every 10 minutes, with no impact on animals survival. "
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    ABSTRACT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective treatment and commonly diagnosed only on late stages. Amyloid-β (Aβ) accumulation and exacerbated tau phosphorylation are molecular hallmarks of AD implicated in cognitive deficits and synaptic and neuronal loss. The Aβ and tau connection is beginning to be elucidated and attributed to interaction with different components of common signaling pathways. Recent evidences suggest that non-fibrillary Aβ forms bind to membrane receptors and modulate GSK-3β activity, which in turn phosphorylates the microtubule-associated tau protein leading to axonal disruption and toxic accumulation. Available AD animal models, ranging from rodent to invertebrates, significantly contributed to our current knowledge, but complementary platforms for mechanistic and candidate drug screenings remain critical for the identification of early stage biomarkers and potential disease-modifying therapies. Here we show that Aβ1-42 injection in the hindbrain ventricle of 24 hpf zebrafish embryos results in specific cognitive deficits and increased tau phosphorylation in GSK-3β target residues at 5dpf larvae. These effects are reversed by lithium incubation and not accompanied by apoptotic markers. We believe this may represent a straightforward platform useful to identification of cellular and molecular mechanisms of early stage AD-like symptoms and the effects of neuroactive molecules in pharmacological screenings.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Although Aβ was discovered over 25 years ago (Goate and Hardy, 2012) and many studies have examined its claimed toxicity, the non-pathological functions of the Aβ peptide are still poorly understood. A study by Cameron et al. (2012) demonstrated that high levels of Aβ can increase cerebrovascular branching in the developing zebrafish hindbrain. They then completed a follow up study to determine whether lowering Aβ levels would have the opposite effect (Luna et al., 2013). "
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    ABSTRACT: Rodent models have been extensively used to investigate the cause and mechanisms behind Alzheimer's disease. Despite many years of intensive research using these models we still lack a detailed understanding of the molecular events that lead to neurodegeneration. Although zebrafish lack the complexity of advanced cognitive behaviors evident in rodent models they have proven to be a very informative model for the study of human diseases. In this review we give an overview of how the zebrafish has been used to study Alzheimer's disease. Zebrafish possess genes orthologous to those mutated in familial Alzheimer's disease and research using zebrafish has revealed unique characteristics of these genes that have been difficult to observe in rodent models. The zebrafish is becoming an increasingly popular model for the investigation of Alzheimer's disease and will complement studies using other models to help complete our understanding of this disease.
    Full-text · Article · Jun 2014 · Frontiers in Genetics
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    • "Studies in zebrafish that express green fluorescent protein in vascular endothelial cells corroborated these results. Treatment with γ-secretase inhibitors or Aβ resulted in significantly more vascular branching in the brain [63]. Studies in various APP mutant AD mouse models have also shown alterations in brain vasculature as a result of Aβ. "
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    ABSTRACT: Growing evidence suggests that vascular perturbation plays a critical role in the pathogenesis of Alzheimer's disease (AD). It appears to be a common feature in addition to the classic pathological hallmarks of amyloid beta (Aβ) plaques and neurofibrillary. Moreover, the accumulation of Aβ in the cerebral vasculature is closely associated with cognitive decline, and disruption of the blood-brain barrier (BBB) has been shown to coincide with the onset of cognitive impairment. Although it was originally hypothesized that the accumulation of Aβ and the subsequent disruption of the BBB were due to the impaired clearance of Aβ from the brain, a body of data now suggests an alternative hypothesis for vascular dysfunction in AD that amyloidogenesis promotes extensive neoangiogenesis leading to increased vascular permeability and subsequent hypervascularization. In this review, we discuss the role Aβ plays in angiogenesis of the neurovasculature and BBB and how it may contribute to the pathogenesis of AD. These studies suggest that interventions that directly or indirectly affect angiogenesis could have beneficial effects on amyloid and other pathways in AD.
    Full-text · Article · Dec 2013 · Alzheimer's Research and Therapy
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