Role of inflammation and other immune responses in Alzheimer’s
Inflammation is the brain’s consistent fundamental response to trauma, whether the challenge is infection or injury. It also has emerged as a necessary component to the pathological cascade of Alzheimer’s, enabling amyloid aggregation and tau propagation to develop into clinically diagnosable disease. However, the roles of each protein—why they exist in the brain at all—and their interrelationship with inflammatory processes still are emerging. Cure Alzheimer’s Fund is supporting efforts to investigate neuroinflammatory processes and feedback mechanisms as well as groundbreaking research uncovering a functional role for amyloid as an infection-fighting agent in the brain.
The laboratory of Rob Moir, Ph.D., recently advanced the novel idea that Abeta is part of the innate immune system and belongs to a family of proteins called antimicrobial peptides (AMPs). Unlike the responsive immune system, which creates antibodies and triggers inflammation, the innate immune system is evolutionarily very ancient and functions by providing an immediate response to pathogens. Because the brain does not have a responsive immune system generating pathogen-specific antibodies like the rest of the body, AMPs function as generic natural antibiotics to protect against invading pathogens. In vitro Abeta can inhibit the growth of at least eight clinically important pathogens. In addition, samples from the brains of AD patients have specific Abeta-mediated antimicrobial activity.
The discovery of Abeta’s role in innate immunity identifies pharmacological manipulation of the innate immune system as a new and promising therapeutic strategy for treating AD.
Abeta Expression Protects the Brain from Herpes Simplex Virus
Alzheimer's disease (AD) is characterized by two hallmark pathologies. The first is accumulation of amyloid-beta peptide (Abeta) outside neurons as insoluble amyloid plaques. The second is aggregation inside of neurons of tau protein as filamentous structures called neurofibrillary tangles. High amyloid loads in brain induce tauopathy and amyloid/tauopathy together appear to cause the neurodegeneration associated with Alzheimer's disease (AD).
Targeting Beneficial Innate Immunity in Alzheimer’s by IRAK-M Deletion
A defining feature of Alzheimer’s disease is brain accumulation of toxic plaques that induce memory loss. In the healthy brain, innate immune cells are protective; however, in Alzheimer patients’ brains, these cells fail to prevent plaque formation. Innate immune cells express a molecule named IRAK-M that ensures immune responses to invading bacteria and viruses are kept under tight control. Yet, this type of immune response is dysfunctional in the Alzheimer patient brain. Our hypothesis is that ‘re-balancing’ the brain’s immune response by blocking IRAK-M will enable plaque clearance.
Impact of Inflammasome Deactivation on Alzheimer’s Disease
This research proposal from the Dixit laboratory, which will be pursued in interdisciplinary collaboration with the lab of Dr. Rudy Tanzi at Massachusetts General Hospital (MGH), emanates from our original findings that NLRP3 inflammasome activation in microglia controls age-related inflammation in the central nervous system (CNS) and that CD33-dependent inhibition of amyloid-beta uptake by microglia reduces IL-1beta to protect against AD.