Grant: Project Grant

Progressive cognitive decline associated with amyloid deposition, neurofibrillary tangles, and neurodegeneration is hallmark of Alzheimer's disease (AD). The cognition impairment in both patients and in rodent models of Alzheimer's disease is related to temporal modulation of neuronal signaling that depends on the balance between neurons that are responsible for excitatory and those mediate inhibitory activity. In Alzheimer's disease patients and in rodent models of AD, it is the inhibitory neurons that are initially dysfunctional and ultimately lost. The loss of inhibitory signals in specific regions of the brain impairs attention and memory processing and retrieval. Furthermore, memory acquisition requires changes in signaling patterns of hippocampal inhibitory interneurons. A variety of cognitive processes including working memory is known to depend on an intact inhibitory network. Historically, the use of drugs targeting inhibitory interneurons as well as exogenous stem cell replacement to address the imbalance of excitatory-inhibitory activity have resulted in severe side-effects. Our treatment strategy to rebalance the neuronal network by induction of cellular conversion of endogenously activated astrocytes into inhibitory neurons that respond appropriately to environment signals represents a critical advance over paradigms investigated to date.