In experiments with mice, researchers have discovered a mechanism by which the toxic brain protein produced in Alzheimer’s disease (AD) could contribute to the cognitive deficits that are its hallmark. They found evidence that the toxic protein, called Aâ peptide, triggers overexcitation of neurons in the brain’s learning centers, inducing compensatory rewiring of brain circuitry in the centers—all of which could cause deterioration of neural function.
The researcher wrote that their results showed the need for studies to explore whether blocking that overexcitation might prevent such neurological deficits in AD.
Lennart Mucke and colleagues published their findings in the September 6, 2007 issue of the journal Neuron, published by Cell Press.
For their experiments, the researchers used mice genetically engineered to produce the human version of the protein that gives rise to Aâ peptide in people with AD. Such mice show neurological abnormalities in learning regions of the brain that parallel those of people with AD.
EEG studies in the mice showed increased seizure activity indicative of neuronal overexcitation—especially significant because people with AD are more prone to seizures. Studies of the neuronal circuitry in learning centers of the animals’ brains showed a rewiring that indicated an imbalance between the normal excitatory and inhibitory neuronal activity. The studies also indicated that the circuitry was remodeling itself to increase inhibitory circuit function.
Significantly, the researchers could induce in normal mice the same molecular and anatomical alterations found in the genetically altered mice by giving them a drug that induces neuronal overexcitation.
What’s more, their studies revealed genetic and biochemical changes in the brains of the engineered mice that indicated abnormal overexcitation of neurons, as well as impaired “plasticity”—the adaptability of neuronal connections that is central to learning.
The researchers wrote that their findings indicated that “cognitive deficits in [the genetically altered] mice, and perhaps also in humans with AD, may result from the combination of neuronal overexcitation and the subsequent development of compensatory inhibitory mechanisms that reduce overexcitation but end up constraining the functional agility of specific excitatory circuits.
They wrote that “Studies are needed to determine whether blocking Aâ-induced neuronal overexcitation can prevent the activation of inhibitory pathways as well as the development of AD-related neurological deficits.”
The researchers include Jorge J. Palop, Jeannie Chin, Erik D. Roberson, Jun Wang, Myo T. Thwin, and Nga Bien-Ly of the Gladstone Institutes and the University of California, San Francisco in San Francisco; Jong Yoo of Baylor College of Medicine in Houston; Kaitlyn O. Ho, Gui-Qiu Yu, Anatol Kreitzer, Steven Finkbeiner of the Gladstone Institutes and the University of California, San Francisco in San Francisco; Jeffrey L. Noebels of Baylor College of Medicine in Houston; and Lennart Mucke of the Gladstone Institutes and the University of California, San Francisco in San Francisco.
This work was supported in part by a fellowship from the McBean Foundation (J.J.P.) and by National Institutes of Health Grants AG023501, AG011385, and NS041787 to L.M., NS29709 and HD24064 to J.L.N., NS39074 and AG022074 to S.F., NS54811 to E.D.R., and a facilities grant (RR 018928) from the National Center for Research Resources.
Palop et al.: “Aberrant Excitatory Neuronal Activity and Compensatory Remodeling of Inhibitory Hippocampal Circuits in Mouse Models of Alzheimer’s Disease.” Publishing in Neuron 55, 697–711, September 6, 2007. DOI 10.1016/j.neuron.2007.07.025. www.neuron.org
Journal
Neuron