Summary: A new study shows that impaired insulin signaling in the brain harms cognition, memory and mood, offering insight into why people with type 2 diabetes face higher risk of developing Alzheimer’s disease.
Source: Joslin Diabetes Center.
Researchers continue to uncover links between type 2 diabetes and Alzheimer’s disease, but the specific mechanisms remain incompletely understood. A new study from Joslin Diabetes Center, an affiliate of Harvard Medical School, provides fresh evidence that impaired insulin signaling in the brain can directly affect learning, memory, mood and metabolic control—key features of Alzheimer’s disease.
Published in the Proceedings of the National Academy of Sciences (PNAS), the study used a novel mouse model to examine how loss of both insulin receptors and insulin-like growth factor 1 (IGF1) receptors in targeted brain regions alters behavior and physiology. Because these two receptors can compensate for one another, the researchers knocked out both receptors simultaneously in specific areas of the brain to reveal the combined effect on cognition and metabolism.
“This was the first time we were able to demonstrate that disrupting both of these signaling pathways—even without other defects—was enough to impair learning and memory,” said C. Ronald Kahn, Chief Academic Officer at Joslin and the Mary K. Iacocca Professor of Medicine at Harvard Medical School, and senior author on the paper. “By removing both the primary receptor and its backup system in targeted regions, we could observe direct impacts on brain function without interfering with overall brain development.”
The team focused the double receptor knockouts on the hippocampus and the central amygdala, two regions central to learning, memory, emotional regulation and metabolic control. Mice lacking both insulin and IGF1 receptors in these areas exhibited a combination of cognitive, mood and metabolic disturbances: impaired performance on memory tasks, altered anxiety- and depression-like behaviors, and changes in glucose regulation.
In one behavioral test, mice were introduced to a maze where they first familiarized themselves with the environment. Later, researchers placed a new object or obstacle in the maze to test whether the mice recognized novelty. While normal mice explored the new object, the receptor-impaired mice often navigated the maze as if nothing had changed, indicating deficits in recognition memory and learning.
“We have previously observed metabolic defects in related experiments and mood disturbances in others, but this study is notable because the same mice showed clear defects in learning and memory as well as metabolism,” Dr. Kahn said. These combined deficits mirror cognitive and emotional impairments commonly associated with Alzheimer’s disease.
People with type 2 diabetes are known to be at greater risk than the general population for developing Alzheimer’s disease. Prior research has linked dysfunction in insulin and IGF1 signaling pathways to premature cognitive decline, dementia, depression and anxiety, and several studies have reported abnormalities in these receptors in the brains of people with both Alzheimer’s disease and type 2 diabetes. The Joslin study is among the first to use targeted regional manipulation to clarify cause-and-effect relationships between receptor dysfunction and cognitive decline.
The researchers identified one potential molecular mechanism underlying the observed cognitive effects: reduced expression of the AMPA-type glutamate receptor GluA1. Lower GluA1 levels could impair synaptic connections that support learning and memory and could also influence brain circuits that regulate mood and metabolic responses. The team notes that additional experiments are needed to confirm the precise role of GluA1 in linking insulin/IGF1 signaling defects to both cognitive decline and metabolic dysfunction.
Next, the researchers plan to breed these insulin/IGF1 receptor knockout mice with mouse models genetically predisposed to Alzheimer’s pathology to study how receptor loss affects disease progression and risk. These experiments aim to illuminate whether impaired insulin signaling in specific brain regions accelerates or worsens Alzheimer’s-related pathology.
Clinically, insulin resistance in humans affects both insulin and IGF1 receptor signaling and has been associated with milder forms of cognitive decline. Understanding how these pathways influence synaptic receptors such as GluA1 and networks governing mood and metabolism could point toward strategies to intervene earlier in at-risk individuals and potentially slow or prevent progression to Alzheimer’s disease.
“With diabetes and obesity, resistance in these signaling pathways may be an important factor in why people with both diabetes and Alzheimer’s disease can experience a faster or more severe course,” Dr. Kahn said. Continued study of insulin and IGF1 signaling in defined brain regions should help clarify therapeutic targets to protect cognition and metabolic health.
About this research
Funding: This work was supported by the German Research Foundation.
Source: Jeffrey Bright, Joslin Diabetes Center. Publisher: Organized by NeuroscienceNews.com. Original Research: The study appears in Proceedings of the National Academy of Sciences (PNAS).
Citation
Joslin Diabetes Center. “Insulin Signaling Failures in Brain Linked to Alzheimer’s.” NeuroscienceNews, February 2019. Study published in PNAS.
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