Abstract

Alzheimer’s disease (AD) is marked by neuritic plaques that contain insoluble deposits of amyloid-β (Aβ), yet the physiological function of this peptide has remained unclear for more than two decades. Using genetics and pharmacology we have established that Aβ plays an important role in regulating capillary bed density within the brain, a function that is distinct from other cleavage products of amyloid precursor protein (APP). APP-deficient zebrafish had fewer cerebrovascular branches and shorter vessels in the hindbrain than wild-type embryos; this phenotype was rescued by treatment with human Aβ peptide, but not a smaller APP fragment called p3. Similar vascular defects were seen in zebrafish treated with a β-secretase inhibitor (BSI) that blocked endogenous Aβ production. BSI-induced vascular defects were also improved by treatment with human Aβ, but not p3. Our results demonstrate a direct correlation between extracellular levels of Aβ and cerebrovascular density in the developing hindbrain. These findings may be relevant to AD etiology where high levels of Aβ in the brain parenchyma precede the development of neuritic plaques and dense aberrantly-branched blood vessel networks that appear between them. The ability of Aβ to modify blood vessels may coordinate capillary density with local metabolic activity, which could explain the evolutionary conservation of this peptide from lobe-finned fish to man.

Highlights

  • Alzheimer’s disease (AD) is the most common cause of dementia in the elderly that currently afflicts more than 5.2 million people in the USA, and 13 million worldwide [1]

  • amyloid precursor protein (APP)-deficient embryos had significantly fewer central artery (CtA) branches off the primordial hindbrain channel (Figure 2C, D) than control embryos (Figure 2A, B) or embryos injected with a scrambled-sequence morpholino

  • To determine whether vascular abnormalities in zAPP-MO embryos were primarily due to Aβ deficiency we treated them with human Aβ (1–42) starting at 2 dpf, when vascular abnormalities could be discerned in zAPP-MO embryos (Figure S3)

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Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly that currently afflicts more than 5.2 million people in the USA, and 13 million worldwide [1]. A definitive pathological feature of AD is neuritic plaques in affected brain areas, which contain insoluble deposits of amyloid-β (Aβ) peptide. Neuritic plaques were first described by Alois Alzheimer [2] more than 100 years ago and Aβ was discovered more than 25 years ago [3], the physiological (i.e. non-pathological) function of Aβ remains enigmatic. Aβ is produced throughout life by the brain, and other tissues, as a product of amyloid precursor protein (APP) proteolysis. Mutations in APP and subunits of the γ-secretase complex are the most common causes of early-onset AD [4]

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