Targeting amyloid propagation in Alzheimer disease: Structures, immunology and extracellular vesicle topology

Dr. Neil Cashman is one of five BC researchers supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

As the incidence of Alzheimer’s disease (AD) continues to increase worldwide, a treatment or prevention for AD is a top priority for medical science. One of the main hallmarks of the disease are protein plaques that form inside the brain, and are believed to be the primary cause of brain cell (neuron) death. Research has shown that the protein, amyloid-β (A-beta) is the main component of these plaques.

 

While there are many forms of A-beta produced by brain cells, the specific one that causes AD is hotly debated by scientists. Dr. Neil Cashman, a neuroscientist and neurologist at the University of British Columbia (UBC) has discovered a novel way of identifying a unique form of A-beta that can become toxic and inflict the damage associated with AD.

 

Cashman, who holds the UBC Canada Research Chair in Neurodegeneration and Protein Misfolding, and his team have discovered immunological compounds that specifically recognize the potentially toxic form of the A-beta protein, and can exclusively detect this form in the brains and spinal fluids of AD patients. Furthermore, Cashman found that normal, healthy control patients did not have this dangerous form of A-beta. It was also found that some healthy people naturally develop immune responses against their A-beta oligomer-specific target.

 

Cashman’s team will exploit this knowledge and their unique tools to learn how toxic A-beta proteins can spread from cell-to-cell and region-to-region in the brain causing AD. The discoveries by Cashman’s lab may provide an effective early diagnostic tool for the disease, and ultimately could lead to the development of a preventative vaccine to neutralize the toxicity of abnormal A-beta, potentially slowing or stopping the spread of neurodegeneration in the brain.

 

End of Award Update

Source: CLEAR Foundation

 

What did we learn?

We know that Abeta oligomers, a “seeding species” in Alzheimer’s disease, are predominantly spread in the brain via naked protein aggregates, and not through extracellular vesicles.

 

Why is this knowledge important?

The development of oligomer-specific antibodies (Acumen, ProMIS Neurosciences) has enabled selective immunotherapies for Alzheimer’s disease that target the toxic molecular species of AD, while sparing precursor protein (APP), Abeta monomers, and Abeta fibrils in the form of plaques. Binding to any of these non-oligomer molelcular species of Abeta lead to adverse effects, most prominently plaque-disruption linked ARIA – a form of neurovascular brain edema.

 

What are the next steps?

Dr. Cashman is now the full-time Chief Scientific Officer of ProMIS Neurosciences, which is conducting IND-enabling studies of the oligomer-specfic antibody PMN310. Human phase 1 trials are set for late 2022 or Q1 2023.

 

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