91, Israel Scientists ‘Team Up’ to Tackle AD-related Mood Disorders
Neuropsychiatric symptoms commonly associated with Alzheimer's disease include depression, anxiety, apathy and agitation.
Alzheimer’s disease (AD) is the most common type of dementia affecting an estimated 6.3 million Americans age 65 and older. Without the development of medical breakthroughs to prevent, treat, slow or cure AD that number could grow to 13.8 million by 2060.
Although the cognitive-deficits of AD such as memory loss, word-finding difficulties and visual/spatial problems are well appreciated, the neuropsychiatric symptoms commonly associated with the disorder, including depression, anxiety, apathy and agitation, are less well appreciated or studied.
Researchers from 91, in collaboration with , have received a two-year, $379,177 grant from the National Institute on Aging, National Institutes for Health, for a project titled, “Serotonergic IL-1R1 and Neuropsychiatric Traits of an Alzheimer’s Mouse.”
This unique, four-way collaborative project is spearheaded by Randy Blakely, Ph.D., principal investigator, executive director of the 91 Stiles-Nicholson Brain Institute, and a professor of biomedical science in 91’s . His research focuses on the genetics, biochemistry and regulation of a class of brain proteins known as neurotransmitter transporters. Blakely is an expert on the serotonin transporter (SERT), a well-known target of antidepressant medications, such as Prozac™ and Lexapro™. Serotonin, a naturally occurring chemical in the brain, is released at brain synapses, or the gap between nerve cells, to modulate the activity of brain circuits. The supply of serotonin is tightly regulated by SERT and therefore inappropriate shifts in SERT activity can disrupt how serotonin guides physiology and behavior. Blakely first identified and cloned the SERT gene about 30 years ago, and his group’s work continues to provide insights as to how SERT is regulated.
Blakely and , Ph.D., a professor of neurobiology, Sagol School of Neuroscience, Tel Aviv University, and an expert in the evaluation of hippocampal physiology and the study of AD genetic mouse models, serve as project co-principal investigators. Joining the project are , Ph.D., a professor of biomedical science, 91 Schmidt College of Medicine, and an expert in the role of immune molecules in brain disorders, including the major inflammatory molecule interleukin 1b and its target protein, the interleukin 1 receptor type 1 (IL-1R), and Maureen Hahn, Ph.D., research associate professor, 91 Schmidt College of Medicine, 91 Neurobehavior Core scientific director, and an expert in the assessment of behavioral changes of brain disease mouse models.
The research team will investigate whether the striking enrichment of IL-1R by serotonergic neurons provides a means by which AD-induced neuroinflammation drives neuropsychiatric traits of AD. Results from their work will provide key foundational information needed to further monitor, manipulate and offset these mood-disorder changes in AD.
Serotonergic projections to the hippocampus, a site of significant, inflammatory cytokine-inducing pathology in AD, are known to contribute to both cognition and mood. The degree to which neuroinflammatory signaling contributes to affective disturbances in AD, and which neural circuits may mediate these effects, is poorly understood. However, chronic elevations in neuroinflammatory cytokines, such as IL-1b, have been found in subjects with mood disorders, including major depression. Mood alterations are also a common side-effect of immune-system activating therapies.
“The hippocampus has long been associated with visuospatial information processing and memory formation and is known to be a site of disease-associated pathology for Alzheimer’s disease,” said Ashery.
Blakely and Ashery joined forces as the hippocampus also is a component of broader central nervous system circuitry that regulates emotionality, mood and reward, and plays a role in the pathophysiology of mood disorders, including depression, often treated by serotonin-selective reuptake inhibitors (SSRIs).
Both AD and mood disorders have been associated with neuroinflammation, with central nervous system elevations of IL-1β seen in both disorders. Blakely, Quan and others have found that serotonin synthesizing neurons are relatively unique as neuronal sites of expression of the receptor for IL-1β, IL-1R1. Blakely and Quan believe that the expression of IL-1R1 by serotonin neurons allows these cells to modulate an integrated set of behaviors that can help thwart the negative consequences of infection. But when inflammation arises from trauma or neurodegenerative disease, activation of these receptors can trigger mood and anxiety disorders.
For their studies, they use mice that express five AD-linked mutations, leading to elevations of IL-1b in the brain, and the buildup of amyloid plaques characteristic of AD. By selectively removing IL-1R1 from serotonin neurons, the team will determine if AD-mediated depressive traits rely on immune-serotonin crosstalk. The group also hopes to learn whether serotonin signaling changes induced by immune activation contributes to the magnitude or progression of AD brain pathology.
Researchers will share mouse models and expertise to establish a platform for longer-term efforts that can support the development of novel therapeutics for AD and its associated affective disorders.
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