Neuron: Amyloid beta-induced neuronal dysfunction progresses Alzheimer's

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Amyloid beta expression in entorhinal cortex neurons initiates neuronal network dysfunction in mouse models with Alzheimer's disease, and targeting the entorhinal cortex region might be of therapeutic benefit, according to research published in the Nov. 4 issue of the journal Neuron.

Amyloid beta 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. Communication between the entorhinal cortex and the hippocampus is 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 entorhinal cortex dysfunction contributes to cognitive decline in Alzheimer's disease or whether early vulnerability of the entorhinal cortex initiates the spread of dysfunction through interconnected neural networks," said the study's senior author Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and professor of neurology and neuroscience at 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 entorhinal cortex, " Mucke added.

Mucke and colleagues found that overexpression of mutant APP/amyloid beta selectively in the entorhinal cortex led to age-dependent deficits in learning and memory along with other behavioral deficits, including hyperactivity and disinhibition. Importantly, these abnormalities were similar to those observed in mouse models of Alzheimer's disease with mutant APP expression throughout the brain.

The researchers also observed abnormalities in the hippocampus, including dysfunction of synapses and amyloid beta deposits in parts of the hippocampus that receive input from the entorhinal cortex.

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