Gene Therapy and Cell Reprogramming For the Aging Brain: Achievements and Promise
Joaquin Pardo, Gustavo R. Morel, Mariana Astiz, Jose I. Schwerdt, Micaela L. Leon, Silvia S. Rodriguez, Claudia B. Herenu and Rodolfo G. Goya
Affiliation: INIBIOLP, Faculty of Medicine, UNLP, CC 455, 1900 La Plata, Argentina.
In the central nervous system, cholinergic and dopaminergic (DA) neurons are among the cells most susceptible
to the deleterious effects of age. Thus, the basal forebrain cholinergic system is known to undergo moderate neurodegenerative
changes during normal aging as well as severe atrophy in Alzheimer’s disease (AD). Parkinson's disease (PD),
a degeneration of nigro-striatal DA neurons is the most conspicuous reflection of the vulnerability of DA neurons to age.
Overall, there is growing evidence that a progressive decline in cognitive function and central DA activity represents basic
features of normal aging both in humans and laboratory rodents. Spontaneous or environmental neurotoxin-mediated exacerbation
of these processes contributes to the symptoms of AD and PD, respectively. In this context, neurotrophic factors
that can prevent or delay the decline in cognitive function and central DA activity are of clinical interest. Among
them, Insulin-like Growth Factor I and Glial cell line-Derived Neurotrophic Factor are emerging as powerful neuroprotective
molecules. This article discusses the experimental evidence supporting the neuroprotective relevance of these and related
factors in the aging brain. The availability of induced pluripotent stem cells offers a new promise for the treatment of
pathologies associated with the loss of specific cell types as for instance, nigral DA neurons (in PD) or basal forebrain
cholinergic neurons (BFCN) in the early stages of AD. Recent studies documenting the use of cell reprogramming for the
generation of multipotent neuronal precursors as well as functional BFCN and DA neurons are reviewed.
Keywords: Aging, alzheimer, gene therapy, cell reprogramming, Parkinson, neurodegeneration, neurotropic factors, transdifferentiation.
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