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Morphological and molecular basis of central nervous system plasticity and regeneration.
Aging well is critical as the population of older Americans begins a rapid expansion. Fortunately, studies are showing that America's older population is becoming healthier and more fit. Yet, Alzheimer's disease (AD), the most common form of dementia, affects as many as four million older persons, is the fourth cause of death and takes over 100,000 lives per year. AD results from abnormal changes in the brain that begin long before memory loss and other clinical symptoms become apparent. The defining characteristics of AD are the presence of senile plaques and neurofibrillary tangles, neuronal death, profound changes in cytoskeletal proteins, multiple neurotransmitters alterations and, most crucial, an intense loss of synapses that correlates well with the degree of dementia. AD can be rightly considered a synapse disease.
The rate at which synapses are lost during AD depends on the extent to which the destructive influences associated with the disease process can be compensated for by the constructive influences associated with endogenous regenerative mechanisms: a net loss of synapses implies a failure of the system to elicit a sufficient compensatory response. Two general approaches can be taken to shift the equilibrium between constructive and destructive influences. First, one can attempt to identify and disrupt biochemical pathways that contribute to the disease process. Alternatively, one can attempt to preserve cognition by stimulating normal compensatory mechanisms.
Can the aged brain compensate for this synapse loss? To answer this question, I have focused my research on the brain responses to selective cell loss, and on the extent to which the aged CNS reacts to signals that can promote synaptogenesis and neural regeneration. Using a variety of techniques (immunocytochemistry, in situ hybridization, tract-tracing methods, molecular biology tools and biochemical procedures), I am examining the effects of hormones, neuronal growth factors and extracellular matrix molecules on sprouting and regeneration in the aged brain. Employing a variety of behavioral tasks, I am studying whether this sprouting will compensate for age- and lesion-related declines in cognition.
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SOME RELEVANT PUBLICATIONS
de Lacalle, S., Hyler, B. and Borowski, T. (2008) Estrogen, Cholinergic System and Cognition. In: Neuroactive Steroids in Brain Function, Behavioral and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment. Michael S. Ritsner and Abraham Weizman, Editors. Chapter 6, pp. 123-141. Springer-Verlag.
Martinez, L. and de Lacalle, S. Astrocytic Reaction to a Lesion, under Hormonal Deprivation. Neuroscience Letters (2007), 415 (2): 190-193. [abstract]
de Lacalle, S. (2006) Estrogen effects on neuronal morphology. Endocrine 29(2):185-190. Special issue on “Reproductive Hormones and Neurodegenerative Disease”. Ed.: P.M. Conn; guest editor: F. V. Nowak. [abstract]
Saenz, C., Dominguez, R. and de Lacalle, S (2006) Estrogen contributes to structural recovery after a lesion; Neurosci. Lett. 392:198-201. [abstract]
Hartonian, I. and de Lacalle, S. (2005) Compensatory changes in cortical cholinergic innervation, following an immunotoxic lesion; Restor. Neurol. Neurosci. 23:87-96. [abstract]
Dominguez, R.D., Jalali, C., and de Lacalle, S. (2004) Morphological effects of estrogen on cholinergic neurons in vitro involves activation of extracellular signal-regulated kinases; J. Neurosci.24:982-990. [abstract]
Counts, S.E., Perez, S.E., Ginsberg, S.D., de Lacalle, S. and Mufson, E.J. (2003) Galanin in Alzheimer's disease; Molecular Interventions 3:137-156. [abstract]
Hartonian, I., Mufson, E.J. and de Lacalle, S. (2002) Long-term plastic changes in galanin innervation in the rat basal forebrain; Neuroscience115:787-795. [abstract]
de Lacalle, S. and Saper, C.B. (2000) CGRP-like immunoreactivity marks putative visceral sensory pathways in human brain; Neuroscience100:115-130. [abstract]
Holmes, T.C., de Lacalle, S., Su, X., Liu, G., Rich, A., and Zhang, S. (2000) Extensive neurite outgrowth and active synapse formation on self-assembling peptide scaffolds; Proc. Natl. Acad. Sci. USA97:6728-6733. [abstract]
Iraizoz, I., Guijarro, J.L., Gonzalo, L.M., and de Lacalle, S. (1999) Neuropathological changes in the nucleus basalis correlate with clinical measures of dementia; Acta Neuropathol.98:186-196. [abstract]
Mentz, S., de Lacalle, S., Baerga-Ortiz, A., Knauer, M.F., Knauer, D.J., and Komives, E.A. (1999) Mechanism of thrombin clearance in human astrocytes; J. Neurochem. 72:980-987. [abstract]
Last updated 03/03/10
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