Tracking early signs of Alzheimer’s pathology in a mouse model

About two-thirds of the risk for Alzheimer’s disease (AD) is thought to arise from genetic influences, but about a third could be influenced by environment and lifestyle, opening the door for behavioral interventions that could delay or prevent pathophysiological changes that occur with AD. Now a new study opens in new tab/window in a mouse model of AD examines the effects of environmental enrichment on AD symptom progression and pathology. The study appears in Biological Psychiatry opens in new tab/window, published by Elsevier.

Gerd Kempermann, PhD, from the German Center for Neurodegenerative Diseases in Dresden, Germany, and senior author of the study, emphasized the importance of studying the early stages of disease, when interventions might be most effective.

Dr. Kempermann commented, “AD does not start when the symptoms become obvious. There is a decades-long silent period, during which the pathology progresses undetected. Clinicians and researchers have become increasingly interested in what happens during this phase.”

To study this early pathology, Dr. Kempermann and colleagues used a mouse model of AD that replicates this silent period. The model contains several mutations associated with human AD in the gene encoding amyloid precursor protein (App). These App^NL-F mice develop toxic amyloid-beta plaques by age 6 months and cognitive impairment by 18 months.

Dr. Kempermann said, “However, we discovered that there are already subtle but important behavioral changes long before the first plaques appear, and the cognitive deficits become detectable.”

The mice were housed in an enriched environment, which consisted of 60 interconnected cages, from age 6 weeks to 23 weeks and were then moved to standard cages after 4 months. Living in the enriched environment improved several measures of metabolism, which are known risk factors for AD.

Dr. Kempermann explained, “The [AD model] mice in our study showed a reduction in individual behaviors. They became more similar and more rigid. As this individualization is to a large degree driven by individual behavior and depends on brain plasticity, we can conclude that the affected mice had behavioral deficits very early in the course of the disease. They did not respond normally to the offerings of their environment. This finding is important, because it will help us to understand how we can best tailor preventive measures during the pre-clinical phase. It also underscores that prevention has to start early.”

The researchers also examined markers of neurogenesis in the mice. Paradoxically, the App^NL-F mice had higher rates of neurogenesis than control mice, which is interpreted as a failing attempt at compensation and as paradoxically counterproductive. This overshooting compensation was normalized by exposure to enrichment.

John Krystal, MD, Editor of Biological Psychiatry, said of the work, "This novel study suggests that environmental enrichment may reduce the early accumulation of amyloid plaques in a mouse model of AD. This insight may suggest a strategy for delaying the development of symptoms associated with this disorder."

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Notes for editors

The article is "Pre-symptomatic reduction of individuality in the App^NL-F knock-in model of Alzheimer’s disease," by Fanny Ehret, Meike S. Pelz, Anna N. Senko, Karla E.G. Soto, Hang Liu, and Gerd Kempermann (https://doi.org/10.1016/j.biopsych.2023.04.009 opens in new tab/window). It appears as an Article in Press in Biological Psychiatry opens in new tab/window, published by Elsevier.

It is openly available at https://www.biologicalpsychiatryjournal.com/article/S0006-3223(23)01205-2/fulltext opens in new tab/window.

Copies of this paper are also available to credentialed journalists upon request; please contact Rhiannon Bugno at +1 254 522 9700 or [email protected] opens in new tab/window. Journalists wishing to interview the authors may contact Gerd Kempermann at +49 351 210 463 700 or [email protected] opens in new tab/window.

The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here opens in new tab/window.

About Biological Psychiatry

Biological Psychiatry opens in new tab/window is the official journal of the Society of Biological Psychiatry opens in new tab/window, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 12^th out of 155 Psychiatry titles and 14^th out of 274 Neurosciences titles in the Journal Citation Reports^TM published by Clarivate Analytics. The 2021 Impact Factor score for Biological Psychiatry is 12.810. www.biologicalpsychiatryjournal.com opens in new tab/window

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