New Take on an Old Disease

Home page Description: 
Researchers reframe Alzheimer disease as an autoimmune disorder and uncover new drug targets.
Image Caption: 
Dr. Donald Weaver is the Director of the Krembil Research Institute and a Senior Scientist at the Krembil Brain Institute.

Alzheimer disease is a common neurodegenerative disorder that causes losses in memory and cognitive function, and eventually death. Treatments for the disease are limited, in part because the mechanisms that trigger the underlying destruction of brain cells are unknown.

An international collaboration led by Dr. Donald Weaver, Director and Senior Scientist at the Krembil Research Institute, has provided a new explanation for how Alzheimer disease develops.

The explanation revolves around a protein building block called amyloid beta, which accumulates in the brains of people with Alzheimer disease and leads to the death of neurons. Despite a growing understanding of amyloid beta, researchers still do not know what causes it to accumulate, and existing treatments targeting it are neither universally accepted nor suitable for all patients.

“We reframed Alzheimer disease as a disorder of the immune system, wherein amyloid beta triggers an immune response that attacks healthy brain cells,” explains Dr. Weaver. “By viewing the disease as an autoimmune disorder, we have united competing theories of what causes the disease into one compelling picture.”

Through a series of experiments and computer simulations of the interactions between amyloid beta and cells, the research team created a four-step model for the development of the disease:

Step 1. In a manner similar to known immune responses, brain cells release amyloid beta in response to invaders such as bacteria and viruses and to traumatic events such as mechanical injury to nearby cells.

Step 2. The amyloid beta behaves similarly to other agents released by the immune system, inserting itself into the membranes of the invading organisms or damaged cells. This action helps to destabilize the unwanted cells and clear them from the body.

Step 3. The amyloid beta mistakenly acts on healthy brain cells because their membranes share traits with those of bacteria and damaged cells.

Step 4. The attacked brain cells degrade and release more amyloid beta, and the cycle repeats itself.

Dr. Weaver’s team proposes that the repetitive release of amyloid beta fuels a self-perpetuating cycle that ultimately causes the progressive neuron degeneration seen in Alzheimer disease.

With their new model, the team sought to identify targets for drugs that could disrupt the cycle. They screened more than 1,100 molecules that naturally occur in the brain as potential targets.

The researchers discovered that biological products made from the amino acid tryptophan are particularly effective in preventing the accumulation of amyloid beta. They then compiled a library of natural and synthetic compounds that might be good candidates for use in therapy because of their similarities to these biological products.

“By uncovering a new dimension to Alzheimer disease and identifying potential therapeutic compounds, this research could lead to a new treatment that can target the underlying driver of the disease to prevent further cognitive changes,” says Dr. Weaver.

This work was supported by the BrightFocus Foundation, Canadian Institutes of Health Research, Alzheimer’s Society of Canada, Ontario Brain Institute, Canada Foundation for Innovation, Sobey Family and Sobey Foundation, Weston Brain Institute, Michael Albert Garron Foundation, Dalhousie Medical Research Foundation, Atlantic Canada Opportunities Agency, Krembil Foundation and UHN Foundation. Dr. Donald Weaver is a Professor of Chemistry, Medicine and Pharmaceutical Science at the University of Toronto.

Meier-Stephenson FS, Meier-Stephenson VC, Carter MD, Meek AR, Wang Y, Pan L, Chen Q, Jacobo S, Wu F, Lu E, Simms GA, Fisher L, McGrath AJ, Fermo V, Barden CJ, Clair HDS, Galloway TN, Yadav A, Campágna-Slater V, Hadden M, Reed M, Taylor M, Kelly B, Diez-Cecilia E, Kolaj I, Santos C, Liyanage I, Sweeting B, Stafford P, Boudreau R, Reid GA, Noyce RS, Stevens L, Staniszewski A, Zhang H, Murty MRVS, Lemaire P, Chardonnet S, Richardson CD, Gabelica V, DePauw E, Brown R, Darvesh S, Arancio O, Weaver DF. Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites. Alzheimers Dement (N Y). 2022 Apr 6. doi: 10.1002/trc2.12283.

The burning of each match sparks the next match, similar to how each cycle of neuron degeneration induced by amyloid beta provokes the next in the new model of Alzheimer disease.