We are interested in understanding the molecular and cellular mechanisms of neurodegeneration in Alzheimer's disease (AD), as well as in other neurodegenerative disorders. For this purpose, we have analyzed the role of abnormal functioning of synaptic proteins both in human brains, for which extensive clinical neuropathological and genetic information was available, as well as in experimental animal models where these synaptic proteins are abnormally expressed.
Role of Synaptic Proteins in Alzheimer's Disease. Previous studies in our laboratory, as well as in other research centers, have shown that cognitive alterations in AD are the result of a progressive synaptic damage that initiates in the entorhinal cortex-perforant pathway circuitry and then extends to the association cortex. These studies have also shown that synaptic damage occurs early in the development of the disease and is a major contributor to the subsequent alterations (neuronal loss and plaque formation). Synaptic damage in AD could be the result of deficient neurotrophic activity and/or widespread neurotoxic effects. Recent studies suggest that abnormal expression and/or processing of growth-associated proteins in the central nervous system (CNS) may play a role in the process leading to synaptic damage and neurodegeneration in AD. Prominent among these is amyloid precursor protein (APP), a molecule centrally involved in AD pathogenesis, since mutations within the gene that encodes for this molecule are associated with familial AD (FAD), and overexpression of mutated APP in transgenic mice results in AD-like pathology. Therefore, to better understand the role of APP in AD pathophysiology, it is important to understand the function of this molecule in normal CNS. In this regard, recent studies have shown that APP is found primarily in neurons with a preferential localization at central and peripheral synaptic sites, suggesting a possible role in neuroplasticity. Furthermore, we have shown that secreted-APP fulfills synaptotrophic and neuroprotective functions within the CNS in response to excitotoxicity and ischemia. In addition, abnormal overexpression of mutant forms of APP in transgenic mice results in neuropathological alterations similar to AD. Therefore, abnormal functioning of secreted-APP may be involved in the mechanisms of synaptic damage by failing to promote or maintain normal synaptic populations after excitotoxic challenge. At the present time, we are in the process of understanding in greater detail the various molecular pathways involved in this process.
Although APP appears to play a central role in the pathogenesis of AD, other neuromodulatory molecules that regulate APP processing might also be involved. We are currently studying in in vitro and in vivo models the role of non-A component of AD amyloid precursor (NACP) and apolipoprotein-E (apoE). Alterations in the functioning of these synapse-related proteins have been also shown to lead plaque formation and synapse damage.
Mechanism of Neurodegeneration in AIDS Dementia Complex. A significant number of patients with AIDS develop neurological complications. Cognitive alterations and, in particular the AIDS dementia complex (ADC) can result from HIV encephalitis (HIVE) in the absence of detectable opportunistic infections or neoplasia. HIVE is characterized by productive infection of cells of monocytic/macrophage lineage in the CNS, accompanied by diffuse and nodular microgliosis, multinucleated giant cell (MNGC) formation, astrogliosis, and myelin pallor. In addition, recent studies have shown that in HIVE there is a progressive loss of specific neuronal populations in the neocortex, limbic system, and basal ganglia in association with synaptic and dendritic damage. Notably, the extent of dendritic and neuronal damage in HIVE was closely correlated with the amount of viral antigen in the brain, as assessed by semiquantitative immunocytochemistry for the HIV. Studies in transgenic mice have confirmed these observations and suggested that the HIV derived protein gp120 plays an important role. At the present time, we are in the process of better understanding the mechanisms through which viral products damage dendritic structure and leads to cognitive dysfunction.
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