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Vulnerable brain region may be central to progression of Alzheimer's disease

Date:
November 7, 2010
Source:
Cell Press
Summary:
New research is helping to unravel the events that underlie the "spread" of Alzheimer's disease (AD) throughout the brain. The research 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 AD originates would be simpler than targeting multiple brain areas.
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3-D image of a mouse brain with the location of the entorhinal cortex (yellow) and hippocampus (purple) highlighted.
Credit: Image courtesy of Gladstone Institute of Neurological Disease

New research is helping to unravel the events that underlie the "spread" of Alzheimer's disease (AD) throughout the brain. The research, published by Cell Press 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 AD originates would be simpler than targeting multiple brain areas.

An alteration in brain levels of amyloid β-proteins (Aβ) plays a major pathogenic role in AD, a devastating neurodegenerative disorder that causes progressive cognitive impairment and memory loss. AD 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 AD is the entorhinal cortex (EC). Communication between the EC and the hippocampus is critical for memory and disruption of this circuit may play a role in memory impairment in the beginning stages of AD. "It is not clear how EC dysfunction contributes to cognitive decline in AD or whether early vulnerability of the EC initiates the spread of dysfunction through interconnected neural networks," explains senior study author, Dr. Lennart Mucke from the Gladstone Institutes and the University of California, San Francisco. "To address these questions, we studied transgenic mice with spatially restricted overexpression of mutant APP primarily in neurons of the EC."

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

"Our findings directly support the hypothesis that AD-related dysfunction is propagated through networks of neurons, with the EC as an important hub region of early vulnerability," concludes Dr. Mucke. "Although additional studies are needed to better understand how events in the EC are related to AD, it is conceivable that early interference in the EC might be of therapeutic benefit, perhaps halting disease progression."


Story Source:

The above post is reprinted from materials provided by Cell Press. Note: Materials may be edited for content and length.


Journal Reference:

  1. Julie A. Harris, Nino Devidze, Laure Verret, Kaitlyn Ho, Brian Halabisky, Myo T. Thwin, Daniel Kim, Patricia Hamto, Iris Lo, Gui-Qiu Yu, Jorge J. Palop, Eliezer Masliah, Lennart Mucke. Transsynaptic Progression of Amyloid-β-Induced Neuronal Dysfunction within the Entorhinal-Hippocampal Network. Neuron, 2010; 68 (3): 428-441 DOI: 10.1016/j.neuron.2010.10.020

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Cell Press. "Vulnerable brain region may be central to progression of Alzheimer's disease." ScienceDaily. ScienceDaily, 7 November 2010. <www.sciencedaily.com/releases/2010/11/101103135239.htm>.
Cell Press. (2010, November 7). Vulnerable brain region may be central to progression of Alzheimer's disease. ScienceDaily. Retrieved July 31, 2015 from www.sciencedaily.com/releases/2010/11/101103135239.htm
Cell Press. "Vulnerable brain region may be central to progression of Alzheimer's disease." ScienceDaily. www.sciencedaily.com/releases/2010/11/101103135239.htm (accessed July 31, 2015).

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