Investigating Mechanisms that Link Diabetes Mellitus and Alzheimer's Disease

Frank LaFerla, PhD
University of California, Irvine (Irvine, CA)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to July 31, 2018
Disease:
Alzheimer's Disease
Award Amount:
$250,000
Grant Reference ID:
A2015535S
Award Type:
Standard
Award Region:
US Southwestern
Frank LaFerla, PhD

Impact of Diabetes on Tau Pathology and Cognition In AD Transgenic Mice

Summary

Alzheimer’s disease (AD) and diabetes mellitus (DM) are two of the most common medical illnesses impacting our society, and recent studies indicate that these two disorders may be related.  This proposal seeks to elucidate how diabetes affects AD.  As part of this project, we have developed innovative new animals model to dissect the molecular pathways by which of diabetes impacts AD. This is important because elucidating these pathways offers real and concrete opportunities to develop novel therapies.

Details

Whereas a small proportion of Alzheimer’s disease (AD) cases are inheritable, the majority of cases occur sporadically. The mechanisms underlying the pathogenesis of sporadic AD are poorly defined, and the current treatments have mild and limited beneficial effects. Epidemiological studies indicate that diabetes mellitus (DM) significantly increases the risk of developing AD. Thus far, most studies investigating the link between AD and DM have focused on DM-mediated effects on amyloid pathology, leaving the effects on tau pathology understudied. Notably, we made the novel discovery that DM promotes AD-like tau pathology in animal models, and that the cognitive deficits induced by type 1 diabetes mellitus (T1DM) are dependent on tau. Therefore, the goal of our current study is to characterize the molecular mediators that underlie the cognitive impairments associated with DM.

Because type 2 diabetes (T2DM) represents the majority of diabetes cases in the US, the first aim of our study investigates whether tau is a key mediator required for T2DM-induced cognitive and synaptic impairments. We hypothesize that genetically deleting tau will mitigate the cognitive deficits induced by T2DM. The results from this experiment will provide critical data regarding the molecular role tau plays in modulating T2DM-mediated impairments in cognition and synaptic function.

For our second aim, we seek to explore the mechanisms by which diabetes (both T1DM and T2DM) induces tau-pathology, and tau-dependent cognitive and synaptic deficits.  First, T1DM will be experimentally induced in our newly developed wild type human tau (htau) mice by streptozotocin (STZ) administration, and T2DM will be modeled by genetically crossing db /db mice to our htau mice.  Using these novel models, we will elucidate the molecular pathways by which DM promotes tau pathology, alters synapse structure, and modulates synaptic proteins and synaptic plasticity. Doing so will facilitate the development of new therapeutics approaches for AD patients with DM by identifying novel targets.

The combined studies proposed in this grant are highly significant, as the number of AD and DM cases continues to grow at an alarming rate, and their potential impact on society will become even more burdensome in coming decades.  The studies build on our novel observations that T1DM impairs cognition through a tau-dependent mechanism.  The proposal will elucidate the molecular connections by which two major human disorders currently plaguing our society interrelate, and shed light on the critical role tau plays on the cognitive decline mediated by DM. This research is critical; the field needs  further studies into the underlying molecular mechanisms by which DM affects the onset and progression of AD. The proposed studies meet this need, as well as introduce previously underexplored hypotheses specifically focused on tau and its subsequent effects on synaptic and cognitive impairments.  Targeting the molecular determinants in the pathways responsible for triggering DM-induced tau pathology holds great potential as a therapeutic intervention strategy for AD patients with diabetes. 

About the Researcher

Frank M. LaFerla is the Hana and Francisco J. Ayala Dean of the University of California, Irvine (UCI) Francisco J. Ayala School of Biological Sciences, as well as Chancellor’s Professor and former chair of the Department of Neurobiology and Behavior since 2011.  He joined UC Irvine in 1995 as an assistant professor in the then-named department of psychobiology. Since that time he has served in numerous leadership roles, including director of UCI MIND (Institute for Memory Impairments and Neurological Disorders), a research center internationally acclaimed for its work on disorders of the brain, particularly those that are age-related. Currently, Dr. LaFerla is the director of the Alzheimer’s Disease Research Center at UCI. 

Dr. LaFerla received his PhD from the University of Minnesota and his Bachelor of Arts degree from St. Joseph’s University in Philadelphia. The broad goal of Dr. LaFerla’s lab is to elucidate the pathophysiological mechanisms underlying neurodegenerative disorders such as Alzheimer’s disease and other dementias by developing and using novel animal models in parallel with studies from affected human subjects.

He has received several honors for his research accomplishments, including the Promising Work Award from the Metropolitan Life Foundation for Medical Research, the Ruth Salta Investigator Achievement Award from the former ly-named American Health Assistance Foundation (now BrightFocus Foundation), the Zenith Fellows Award from the Alzheimer Association, and from his own institution the UCI Innovators Award and the Senate Distinguished Mid-career Faculty Research Award.

Dr. LaFerla is a fellow of the American Association for the Advancement of Science and an elected member of the American Neurological Association, the American Society for Cell Biology, the International Society for Stem Cell Research, and the Society for Neuroscience. He is a frequent guest speaker at local, national, and international venues, and is a current member of the board of directors of the Orange County Alzheimer’s Association.



"Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease affecting the very essence of what makes an individual unique.  Unfortunately, current treatments offer no preventive effect, nor can they delay its progression. Seeing how this devastating disease affects several of my relatives has provided my motivation to find a way to prevent, or possibly cure this devastating neurological disorder.  I press forward with research today, knowing that the work we do and the discoveries we make fuel the hope of tomorrow for a world without Alzheimer’s disease.

Now is the time to increase the support for research into new therapeutics, and to advance the understanding of how concomitant diseases may accelerate AD onset. The insightful staff and scientific experts of the BrightFocus Foundation have recognized that studies exploring the relationship between AD and diabetes are critical."

Publications

Rodriguez-Ortiz CJ, Prieto GA, Martini AC, Forner S, Trujillo-Estrada L,LaFerla FM, Baglietto-Vargas D, Cotman CW, Kitazawa M. miR-181a negatively modulates synaptic plasticity in hippocampal cultures and its inhibition rescues memory deficits in a mouse model of Alzheimer's disease. Aging Cell. 2020 Feb 22:e13118. doi: 10.1111/acel.13118. [Epub ahead of print] PubMed PMID: 32087004 PubMed Icon Google Scholar Icon

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