Gladstone Scientists Identify Process By Which Alzheimer's Disease Creeps Through the Brain

SAN FRANCISCO, CA—November 3, 2010—Scientists at the Gladstone Institute of Neurological Disease (GIND) have offered new information about the events that underlie the “spread” of Alzheimer's disease throughout the brain. The research, published in the November 4th issue of the journal Neuron, follows disease progression from a vulnerable brain region that is affected early in the disease to interconnected brain regions that are affected in later stages. The findings may contribute to design of therapeutic interventions, as targeting the brain region where Alzheimer's disease originates might be simpler than targeting multiple brain areas.

An alteration in brain levels of amyloid β proteins (Aβ) plays a major role in Alzheimer's disease, a devastating neurodegenerative disorder that causes progressive cognitive impairment and memory loss. Alzheimer's disease is characterized by abnormal accumulation of Aβ in the brain, which leads to the formation of protein aggregates that are toxic to neurons. Aβ peptides are generated when a large protein called amyloid precursor protein (APP) is cut up into smaller pieces.

One of the first brain regions affected in Alzheimer's disease is the entorhinal cortex (EC). Connections between the EC and another brain region called hippocampus are critical for memory, and disruption of this circuit may play a role in memory impairment in the beginning stages of Alzheimer's disease.

“It is not clear how EC dysfunction contributes to cognitive decline in Alzheimer's disease or whether early vulnerability of the EC initiates the spread of dysfunction through interconnected neural networks,” explained senior study author and GIND director Lennart Mucke, MD. “To address these questions, we studied transgenic mice with mutant APP expressed primarily in neurons of the EC.”

The majority of current mouse models of Alzheimer's disease express mutant proteins throughout the brain, making it difficult to identify the role of any specific brain region in Alzheimer's disease-related dysfunction.

Dr. Mucke and colleagues found that expressing mutant APP and Aβ selectively in the EC led to age-dependent deficits in learning and memory, and other behavioral deficits including hyperactivity and disinhibition. Importantly, these abnormalities are similar to those observed in mouse models of Alzheimer's disease with mutant APP expression throughout the brain. The researchers also observed abnormalities in parts of the hippocampus that receive input from the EC, including dysfunction of synapses and Aβ deposits.

“Our findings directly support the hypothesis that Alzheimer's disease-related dysfunction is propagated through networks of neurons, with the EC as an important hub region of early vulnerability,” concluded Dr. Julie Harris, the lead author of the study. “Although additional studies are needed to better understand how events in the EC are related to Alzheimer's disease, it is conceivable that early interference in the EC might be of therapeutic benefit, perhaps halting disease progression.”

Also contributing to this study were Gladstone scientists Nino Devidze, Laure Verret, Kaitlyn Ho, Brian Halabisky, Myo T. Thwin, Daniel Kim, Patricia Hamto, Iris Lo, Gui-Qiu Yu, Jorge J. Palop, and Professor Eliezer Masliah of the University of California at San Diego.

The study was supported by grants from the National Institutes of Health and a fellowship from the McBean Foundation.

Lennart Mucke's primary affiliation is with the Gladstone Institute of Neurological Disease, where he is Director/Senior Investigator and where his laboratory is located and his research is conducted. He is also the Joseph B. Martin Distinguished Professor of Neuroscience at UCSF.

Gladstone Institutes is a nonprofit, independent research and educational institution, consisting of the Gladstone Institute of Cardiovascular Disease, the Gladstone Institute of Virology and Immunology, and the Gladstone Institute of Neurological Disease. Independent in its governance, finances and research programs, Gladstone shares a close affiliation with UCSF through its faculty, who hold joint UCSF appointments.

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