Abstract
This paper reports critical tests of a novel hypothesis that proposes a molecular mechanism of unhealthy brain aging and possibly, Alzheimer's disease. For more than 30 years, evidence has been accumulating that brain aging is associated with dysregulation of calcium in neurons. Recently, we found that FK506-binding protein 12.6/1b (FKBP1b), a small protein that regulates calcium, declines with aging in the hippocampus, a brain region important for memory. Here we used gene therapy approaches and found that raising FKBP1b reversed calcium dysregulation and memory impairment in aging rats, allowing them to perform a memory task as well as young rats. These studies identify a potential molecular mechanism of brain aging and may also have implications for treatment of Alzheimer's disease.
Highlights
The population of developed nations is projected to age significantly over the several decades
We induced FK506-binding protein 12.6/1b (FKBP1b) overexpression in the hippocampus of male Fischer 344 (F344) rats using one-time microinjection of a recombinant adeno-associated viral (AAV) vector construct containing the transgene for rat FKBP1b under the control of the largely neuron-specific Ca 2ϩ-calmodulin kinase II (CaMKII) promoter
For the first time, that in aged rats in which hippocampal ryanodine receptors (RyRs)-mediated Ca 2ϩ transients and the Ca 2ϩ-dependent slow afterhyperpolarization (sAHP) are normally increased, hippocampal overexpression of FKBP1b dramatically reduced these responses, restoring them to levels found in young rats
Summary
The population of developed nations is projected to age significantly over the several decades. This article is freely available online through the J Neurosci Author Open Choice option. Tive disorders, a corollary of this increase in population age will be a substantial rise in the prevalence of cognitively impaired individuals and a resulting enormous socioeconomic burden
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