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Cessation of neoangiogenesis in Alzheimer's disease follows amyloid-beta immunization.

ABSTRACT: Pathogenic neoangiogenesis in Alzheimer's disease (AD) is due to amyloid-beta (A?) and results in blood-brain barrier (BBB) leakiness in AD. It likely occurs as a compensatory response to impaired cerebral blood flow and provides a strong link between brain vascularity and AD. A? immunotherapy is an experimental treatment for AD; however, unexpected negative vascular side effects seen in early human clinical trials demonstrate that our knowledge of A? and AD pathogenesis is incomplete. We demonstrate that immunization with A? peptides neutralizes the amyloid trigger leading to neoangiogenesis and reverses hypervascularity in Tg2576 AD mice. This process resolves plaque burden suggesting that neoangiogenesis is a key mechanism underlying plaque formation. A meta-analysis demonstrated that hypervascular reversion in vaccinated Alzheimer's patients. This appears to be the first example of vascular reversion following any therapeutic intervention and supports the conclusion that modulation of neoangiogenesis may repair damage in the AD brain.

SUBMITTER: Biron KE

PROVIDER: S-EPMC3584312 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Cessation of neoangiogenesis in Alzheimer's disease follows amyloid-beta immunization.

Biron Kaan E KE Dickstein Dara L DL Gopaul Rayshad R Fenninger Franz F Jefferies Wilfred A WA

Scientific reports 20130101

Pathogenic neoangiogenesis in Alzheimer's disease (AD) is due to amyloid-beta (Aβ) and results in blood-brain barrier (BBB) leakiness in AD. It likely occurs as a compensatory response to impaired cerebral blood flow and provides a strong link between brain vascularity and AD. Aβ immunotherapy is an experimental treatment for AD; however, unexpected negative vascular side effects seen in early human clinical trials demonstrate that our knowledge of Aβ and AD pathogenesis is incomplete. We demons ...[more]

PMID: 23446889

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Project description:BackgroundAlzheimer's disease (AD) is the most frequently diagnosed neurodegenerative disorder affecting humans, with advanced age being the most prominent risk factor for developing AD. Despite intense research efforts aimed at elucidating the precise molecular underpinnings of AD, a definitive answer is still lacking. In recent years, consensus has grown that dimerisation of the polypeptide amyloid-beta (Aß), particularly Aß₄₂, plays a crucial role in the neuropathology that characterise AD-affected post-mortem brains, including the large-scale accumulation of fibrils, also referred to as senile plaques. This has led to the realistic hope that targeting Aß₄₂ immunotherapeutically could drastically reduce plaque burden in the ageing brain, thus delaying AD onset or symptom progression. Stochastic modelling is a useful tool for increasing understanding of the processes underlying complex systems-affecting disorders such as AD, providing a rapid and inexpensive strategy for testing putative new therapies. In light of the tool's utility, we developed computer simulation models to examine Aß₄₂ turnover and its aggregation in detail and to test the effect of immunization against Aß dimers.ResultsOur model demonstrates for the first time that even a slight decrease in the clearance rate of Aß₄₂ monomers is sufficient to increase the chance of dimers forming, which could act as instigators of protofibril and fibril formation, resulting in increased plaque levels. As the process is slow and levels of Aβ are normally low, stochastic effects are important. Our model predicts that reducing the rate of dimerisation leads to a significant reduction in plaque levels and delays onset of plaque formation. The model was used to test the effect of an antibody mediated immunological response. Our results showed that plaque levels were reduced compared to conditions where antibodies are not present.ConclusionOur model supports the current thinking that levels of dimers are important in initiating the aggregation process. Although substantial knowledge exists regarding the process, no therapeutic intervention is on offer that reliably decreases disease burden in AD patients. Computer modelling could serve as one of a number of tools to examine both the validity of reliable biomarkers and aid the discovery of successful intervention strategies.

Dataset Information

Cessation of neoangiogenesis in Alzheimer's disease follows amyloid-beta immunization.

Publications

Cessation of neoangiogenesis in Alzheimer's disease follows amyloid-beta immunization.

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