Cerebrum DAO

1. Neuroinflammation

Neuroinflammatory changes in Alzheimer's Disease (AD) and other dementias are characterized by the activation of glial cells, particularly microglia and astrocytes, and the release of inflammatory mediators, which contribute to disease progression and severity. The continued release of pro-inflammatory cytokines and associated neurotoxins from microglia serves to exacerbate the neuroinflammation and contribute to neurodegeneration, leading to the activation of yet more microglia. We seek to fund projects that search for inhibitors of neuroinflammation and novel biomarkers specific to neuroinflammation.

2. Metabolic alterations, reactive oxygen species, and mitochondrial dysfunction

Hundreds of metabolites are altered in the brain affected by AD (1). Metabolic alterations, Reactive Oxygen Species (ROS), and mitochondrial dysfunction are interconnected processes that occur early and play a significant role in neurodegeneration. Altered bioenergetic pathways, including glycolysis, branched-chain amino acid metabolism, cholesterol, mitochondrial oxidation, and osmotic alterations are closely correlated with cognitive decline. An imbalance between the production of ROS and the ability of cells to detoxify them can lead to increased inflammatory responses and promote aging-related neurodegeneration. We are seeking proposals targeting early metabolic alterations, with a specific interest in mitochondrial dysfunction.

3. Blood-Brain Barrier (BBB)

The BBB is a highly selective, semipermeable structural and chemical barrier that ensures a stable environment for the brain. However, in AD, the BBB becomes dysfunctional, leading to the failure of Amyloid-Beta (Aβ) transport from the brain to the peripheral circulation. This dysfunction is associated with decreased levels of low-density Lipoprotein Receptor-related Protein 1 (LRP-1) and increased levels of the Receptor for Advanced Glycation End-products (RAGE), which are involved in Aβ transport across the BBB. Aβ deposition in the vasculature leads to pro-inflammatory, cytotoxic events and is associated with cerebral blood flow reductions and impaired hemodynamic responses. We seek proposals targeting early BBB changes and novel BBB disruption biomarkers.