Challenging dogma: Jefferies and colleagues uncover new insights into the pathogenesis of Alzheimer’s Disease

Several hypotheses have been proposed to explain the changes in the brain that are associated with Alzheimer’s Disease (AD).  A UBC team led by CBR investigator Dr. Wilf Jefferies has performed studies in mice and humans that challenge current dogma and reveal new ideas as to the underlying cause of the brain dysfunction. They show that in response to abnormal forms of amyloid in the brain, new vessels form that are leaky, allowing plaques to form which cause damage to neurons. The novel findings uncover a link between angiogenesis and AD and provide new research directions toward effective therapies.

There are several hypotheses surrounding the cause of Alzheimer’s Disease. These attempt to account for the pathologic findings in the brain which include, in particular, plaques and tangles, as well as leaky blood vessels. According to the “vascular hypothesis”, the leakiness of the vessels, believed to contribute to disease progression, is due to hypoxia and neuroinflammation that leads to vascular deterioration and apoptosis. Studies performed by Kaan Biron and colleagues in New York, all led by Wilfred Jefferies, a member of the CBR, recently challenged this theory and have thus provided a novel and important paradigm.

In a recent publication in PLoS One, they showed that the amyloidogenesis that is associated with Alzheimer’s Disease, mediates disruption of the blood brain barrier and promotes vessel leakiness. How does this occur? The amyloidogenesis actually promotes new blood vessel formation (neoangiogenesis) and hypervascularity that results in the redistribution of the so-called tight junctions that otherwise maintain the integrity of the blood brain barrier. These data are novel because they demonstrate how a mutant form of amyloid precursor protein (APP-sw) that in some patients is associated with Alzheimer’s Disease, may induce angiogenesis, hypervascularity and vessel leakiness which in turn may result in plaque formation and neurotoxicity. Although the principal studies were performed in mice, Biron et al corroborated their findings in humans, using postmortem speciments.

The findings are notable for several reasonas. First, they highlight how important it is to question and to challenge dogma. Second, by establishing a stronger link between angiogenesis and Alzheimer’s Disease, they encourage a re-evaluation of some of the data in the field in terms of the role of blood vessels. Finally, they reveal new pathways that might be more amenable to early diagnosis and/or therapy.

These studies were funded in part by the CIHR and the Canadian Stroke Network. The work is highlighted in the Alzheimer Research Forum:

Get the whole story here.

Leave a Reply