Journal
NEUROMOLECULAR MEDICINE
Volume 12, Issue 1, Pages 48-55Publisher
HUMANA PRESS INC
DOI: 10.1007/s12017-009-8097-7
Keywords
Alzheimer's disease; Network dysfunction; Amyloid-beta; Synaptic depression; A beta-induced epileptiform activity; Cognitive decline
Categories
Funding
- National Institutes of Health [AG022074, NS041787]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS041787] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG022074] Funding Source: NIH RePORTER
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Neurodegenerative diseases, including Alzheimer's disease (AD), target specific and functionally connected neuronal networks, raising the possibility that neurodegeneration may spread through abnormal patterns of neural network activity. AD is associated with high levels of amyloid-beta (A beta) peptides in the brain, synaptic depression, aberrant excitatory neuronal activity, and cognitive decline. However, the relationships among these alterations and their underlying mechanisms are poorly understood. In experimental models of AD, high concentrations of pathogenic Ab assemblies reduce glutamatergic transmission and enhance long-term depression at the synaptic level. At the network level, they cause dysrhythmias, including neuronal synchronization, epileptiform activity, seizures, and postictal suppression. Both synaptic depression and aberrant network synchronization likely interfere with activity-dependent synaptic regulation, which is critical for learning and memory. Abnormal patterns of neuronal activity across functionally connected brain regions may also trigger and perpetuate trans-synaptic mechanisms of neurodegeneration. It remains to be determined if synaptic depression and network dysrhythmias are mechanistically related, which of them is primary or secondary, and whether normalization of one will prevent the other as well as cognitive dysfunction in AD.
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