We are pleased to share the five research studies that are being funded through the 2023 Djavad Mowafaghian Centre for Brain Health Alzheimer Disease Research Grant. Each of these projects has the potential to transform Alzheimer disease outcomes. Below is a list of the successful applications along with a brief description of each project. Congratulations to the winning research teams!
The contribution of metabotropic glutamate receptor 5 to impaired neurovascular coupling in Alzheimer disease
Metabotropic glutamate receptor 5 (mGluR5) is a type of protein found in the brain that plays an important role in controlling how brain cells communicate and form memories. In Alzheimer disease, amyloid-beta (Aβ42) builds up in the brain and causes damage, disrupting the normal functioning of mGluR5 in astrocytes, which are brain cells that play a key role in cerebral blood flow.
The research team has shown that when they block or reduce the activity of mGluR5, it can lead to improvements in memory and brain pathology in mice with Alzheimer disease. This suggests that targeting mGluR5 could be a promising approach to reverse some of the harmful effects triggered by Aβ42 in the brains of people with Alzheimer disease.
The goal of this project is to understand how Aβ42 affects mGluR5 signaling in astrocytes of male and female mice. The research team aims to find out if the changes in mGluR5 signaling contribute to problems with blood flow in the brain and cognitive function in both male and female mice with Alzheimer disease, and whether this is regulated by sex hormones.
A universal Drosophila platform for testing modifiers of tau toxixity in tauopathy
Research team: Douglas Allan, Amrit Mudher, Philip Williamson and Efthimios Skoulakis
The microtubule associated protein tau (MAPT) plays a role in certain brain disorders, however it’s not yet understood how the various factors involved in these disorders result in harm to the brain. In addition, one of the challenges is a lack of a single model that allows for the flexible, controlled introduction and testing of different levels of tau variants along with these factors in a living brain as it ages.
This project will use fruit flies (Drosophila) as a model organism to create a flexible, cost-effective and easy-to-use system for studying different factors involved in brain disorders. By using flies, researchers can genetically modify them to test various combinations of these factors in living, aging brain circuits. The goal of this project is to develop the platform’s core molecular genetic reagents. This includes creating a set of genes that allow for the control of the production of different versions of tau protein in the flies, as well as additional genes that allow for the modification of the tags or switches that control the tau genes.
Validating ZDHHC21 as a therapeutic target for Alzheimer Disease
Research team: Shernaz Bamji and Steven Hallam
ZDHHC21 is an enzyme that plays a role in a process called palmitoylation, which affects how proteins function in our cells. This process can influence important cellular activities like protein movement, localization, stability and activity. There is increasing evidence suggesting that disruptions in palmitoylation, specifically the function of ZDHHC21, may contribute to the development of neurodegenerative disorders such as Alzheimer disease (AD).
The research team hypothesizes that the ZDHHC21 protein may accumulate with age due to dysregulation of its turnover process. This protein accumulation could contribute to various pathological features of AD, such as the formation of amyloid-beta plaques, neurofibrillary tangles, and loss of synapses in the brain.
This project’s main goal is to understand how ZDHHC21 is involved in the formation of amyloid-beta and synapse elimination and to find compounds that can help normalize synaptic connectivity and amyloid-beta formation in rat cortical cultures.
The role of Inflammatory bowel disease in the development of Alzheimer disease
People with inflammatory bowel disease (IBD) have a six-fold increased risk of developing Alzheimer disease (AD) and develop AD seven years earlier on average. IBD is a complex disease that causes dysregulation of gut health and results in altered metabolite production by microbiota and inflammation.
The research team hypothesizes that IBD onset in early life produces altered microbiome signaling and chronic inflammation that disrupts microbiota-microglia communication, increasing risk of AD onset. To better understand how IBD affects the development of Alzheimer’s, the team will create a new model that combines the transplantation of human gut bacteria from patients with IBD or healthy individuals into either normal mice or mice genetically modified to have AD.
By examining how gut inflammation in IBD can increase the risk of AD, researchers can identify actionable treatments for future human studies targeting specific relevant microbiota with manipulations of diet, pre or postbiotics.
Disrupting GluA1-VCP/p97 as a novel therapeutic strategy to restore synaptic plasticity in Alzheimer disease
Researcher: Sriram Subramaniam
In Alzheimer disease, the accumulation of amyloid-beta disrupts the signaling and movement of excitatory glutamate receptors called AMPARs which are important for normal brain function. As a result of these disruptions, individuals with AD experience neuronal cell death due to weakened synapses. Recent research has identified a protein called VCP/p97, which plays a role in regulating the movement of AMPARs. It was found that VCP/p97 can retain and release a specific type of AMPAR called GluA1, affecting their activity at synapses. Understanding this mechanism opens up new possibilities for developing treatments that target these interactions and potentially improve the symptoms of AD.
The main goal of this research project is to understand and identify the specific interactions between GluA1 and VCP/p97 proteins at atomic resolution, using cryo-electron microscopy (cryo-EM) and artificial intelligence (AI). By analyzing this structure, researchers aim to develop new drugs that can disrupt the interaction between these proteins in a highly targeted way, using structure-guided drug design and in vitro experiments.
The objective is to enhance the insertion of homo-GluA1 receptors into the cell membranes at the postsynaptic density region in the brain and restore synaptic plasticity caused by problems with the movement of AMPAR receptors in Alzheimer disease.