The major pathological alterations of Alzheimer's disease are neurofibrillary tangles and neurotic plaques. In addition, there is a recently-described accumulation of both amyloid protein and abnormal neurites in the neuropil. The goal of this application is to examine the anatomical relationships of these pathological changes to one another in the perspective of known neural system anatomy. The central hypothesis is that these pathological changes disrupt behaviorally important neural systems by involving their projection neurons, axons and dendrites, and terminal zones. The applicant's previous histopathological studies have suggested that particular projection neurons in the hippocampal formation characteristically and specifically undergo neurofibrillary degeneration. The studies outlined will build on these results by examination of the anatomical correlates of Alzheimer-related pathology in the hippocampal formation, amygdala, temporal neocortex and portions of the diencephalon using both immunohistochemical and histopathological methods. These areas are selected because they are established sites of Alzheimer-related pathology, are areas where the anatomical connection of neural systems have been documented in homologous regions in nonhuman primates, and are areas likely relevant to understanding Alzheimer-related cognitive changes. The exact cytoarchitectural and laminar location of neurofibrillary tangles and neuritic plaques will be determined by histochemical techniques. The localization of amyloid core protein (A4 immunoreactivity), neuritic fibrils in the neuropil (tau and Alz-50 immunoreactivity) and synaptosomal protein markers (synaptophysin and S7B8 immunoreactivity) will be determined by immunohistochemistry. These data will be used to test the specific hypotheses that (1) neurofibrillary tangles occur predominantly in cortical projection neurons; (2) neuritic plaques and amyloid protein occur in the terminal zone of degenerating neurons; (3) the diffuse neuropil alteration represents dystrophic dendrites and axons of affected neurons; and (4) there is a loss of synaptosomal markers in terminal zones of neurons undergoing neurofibrillary degeneration. A potential further benefit of these studies is the identification of specific neuronal populations that consistently undergo neurofibrillary degeneration. This can be used to establish a hierarchical table of relative vulnerability, and provide a construct to assess putative markers of neuronal degeneration by identifying neurons likely to be at risk for neurofibrillary changes. These studies hold the promise of defining, on a neural systems level, the anatomical relationships between the major histopathological markers of Alzheimer's disease. Moreover, these studies provide an opportunity to understand the contribution of these pathological changes to the demential of Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Neurology A Study Section (NEUA)
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Massachusetts General Hospital
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Griciuc, Ana; Serrano-Pozo, Alberto; Parrado, Antonio R et al. (2013) Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78:631-43
Serrano-Pozo, Alberto; Muzikansky, Alona; Gómez-Isla, Teresa et al. (2013) Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease. J Neuropathol Exp Neurol 72:462-71
Kopeikina, Katherine J; Polydoro, Manuela; Tai, Hwan-Ching et al. (2013) Synaptic alterations in the rTg4510 mouse model of tauopathy. J Comp Neurol 521:1334-53
Serrano-Pozo, Alberto; Gómez-Isla, Teresa; Growdon, John H et al. (2013) A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 182:2332-44
Kopeikina, Katherine J; Wegmann, Susanne; Pitstick, Rose et al. (2013) Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy. PLoS One 8:e80834
Wu, Hai-Yan; Hudry, Eloise; Hashimoto, Tadafumi et al. (2012) Distinct dendritic spine and nuclear phases of calcineurin activation after exposure to amyloid-? revealed by a novel fluorescence resonance energy transfer assay. J Neurosci 32:5298-309
de Calignon, Alix; Polydoro, Manuela; Suárez-Calvet, Marc et al. (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73:685-97
Tai, Hwan-Ching; Serrano-Pozo, Alberto; Hashimoto, Tadafumi et al. (2012) The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol 181:1426-35
Koffie, Robert M; Hashimoto, Tadafumi; Tai, Hwan-Ching et al. (2012) Apolipoprotein E4 effects in Alzheimer's disease are mediated by synaptotoxic oligomeric amyloid-?. Brain 135:2155-68
Rudinskiy, Nikita; Hawkes, Jonathan M; Betensky, Rebecca A et al. (2012) Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease. Nat Neurosci 15:1422-9

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