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Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Individuals with DS exhibit a very early onset of AD neuropathology, byt heir mid to late 30's. Extra copies of the genes on chromosome 21 may play an important role in this accelerated onset of AD in DS individuals. The amyloid precursor protein (APP) is located on chromosome 21, and among its cleavage products is amyloid-beta (Aß), a component of amyloid plaques. The presence of Aß and amyloid in the brain is a key pathogenic factor, and is considered the central and causative neuropathology in AD by the amyloid cascade hypothesis. Growing evidence suggests an important role for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromsome 21, and is believed to participate in the maintenance of cholesterol homeostasis. The effects of ABCG1 expression on the production of Aß have proved inconclusive in in vitro studies, demanding an in vivo resolution where appropriate physiology is maintained. To test the hypothesis that overexpression of ABCG1 will accelerate the onset or progression of AD in vivo, we evaluated the cognitive performance of ABCG1-overexpressing mice before and after crossing to the PDAPP mouse model of AD. Both normal and AD mice overexpressing ABCG1 showed no significant deficits on several cognitive tests, including reference and working memory task variations of the Morris Water Maze. Golgi analysis of neuronal structure revealed significantly reduced dendritic complexity in both normal and PDAPP mice overexpressing ABCG1, suggesting that the cholesterol-related functions of ABCG1 have a potentially important role in dendrite development. Interestingly, behavioural analysis of ABCG1-deficient mice revealed a gene-dose dependent trend toward worsened performance on the water maze probe trial, suggesting that the pathways that may compensate for ABCG1 overexpression could be unable to offset a complete deficiency. These experiments suggest an important role for ABCG1 in maintaining cellular cholesterol homeostasis, but do not support the hypothesis that ABCG 1 expression contributes to the accelerated onset of AD pathology in DS individuals.

Alzheimer’s disease (AD) is a neurologically debilitating disease that is plaguing our elderly population. Transgenic mice with Alzheimer’s disease mutations are used to study signal pathways, potential drug targets and mechanism of disease. However, studies of the effects of different AD mutations on behavior and neuropathological progression in mice have been inconsistent when comparing different genetic backgrounds. The aim of this study was to compare two commonly used TgCRND8 backgrounds, the 129SvEvtac/C57F1 and C3H/C57F1 strains, for memory function in the Morris water maze (MWM), and to determine differences in plaque burden. We found deficits in multiple parameters of the MWM in the 129SvEvtac/C57F1 strain. Similarly, this background strain showed significantly more amyloid beta (Aβ) plaque burden than the C3H/C57F1 strain. This supports the hypothesis that strain specific differences are apparent in spatial memory testing and neuropathologic progression of AD. It leads us to believe that epigenetics are key to understanding AD risk assessment and development.

The present study considered the notion that Neuropsychological subgroups exist within the diagnosis of Dementia of the Alzheimer's Type (DAT). Specifically, the scores on the Cognitive Examination (CAMCOG) of the Cambridge Index of Mental Disorders in the Elderly for 51 DAT patients and 79 normal adults were analyzed via cluster analysis in an attempt to derive meaningful groupings of patients.Results suggested that the CAMCOG was effective in separating normal from impaired individuals. The results also suggested the existence of 4 subgroups within DAT, which were best interpreted as "levels" or "degrees" of impairment. These levels were characterized by distinctly different CAMCOG subscale profiles. Higher performing groups overall showed greatest deficits in memory functions. The most severely impaired group was characterized by dramatically poorer language skills. Mean ages of the DAT groups was similar so that age alone did not appear to contribute to cluster differences. Moreover, information regarding time since onset of symptoms did not suggest that poorer performance was merely a function of the length of time the disease had progressed. A discriminant analysis revealed that the CAMCOG subscales most effective in separating the groups overall were Abstract Thinking, Orientation, Recent Memory, Learning Memory and CAMCOG total score. The CAMCOG appeared to offer some utility in identifying demented patients and in further describing their varied neuropsychological strengths and weaknesses. Implications for using the CAMCOG in planning for care of DAT patients was discussed. Further research is needed to determine other underlying functions contributing to cluster differences and in identifying everyday functional skills of persons with a given CAMCOG profile. / Department of Educational Psychology

Alzheimer’s disease (AD), a neurodegenerative disorder initially characterized by mild memory impairments, progresses to global cognitive deficits and eventually death. AD pathological hallmarks are plaques and tangles. Acute and chronic effects of familial Alzheimer’s disease (FAD) genes were examined in WT and transgenic mice respectively. We used viral vectors to acutely express FAD genes encoding the Swedish, Indiana, and Swedish and Indiana double mutation, of amyloid precursor protein (APP) in the hippocampal CA1 region (which exhibits early AD pathology) in mice. Acute expression of FAD genes produced deficits in the formation but not retreival of spatial memory. We next examined spine density as changes are thought to affect synaptic plasticity. Acute expression of FAD genes did not affect the structure (dendritic length, intersections and nodes), but decreased spine density in infected CA1 neurons. Amyloid beta (Aβ) binds to excitatory synapses, particularly to GluA2-AMPA receptors (AMPAR) leading to endocytosis. Therefore,, acute CA1 expression of FAD genes produced spatial memory formation deficits mediated by impairments in dendritic spine plasticity and transmission via AMPAR endocytosis. Additionally, infusing GluA2-3Y, a peptide that prevents Aβ induced AMPAR endocytosis in acute and chronic (TgCRND8) AD mouse models expressing double mutated APP genes, was similarly able to rescue the spatial memory and spine density deficits. Since the transcription factor CREB is critical for normal memory formation across species, we investigated its role in TgCRND8 mice. We observed additional deficits in the dorsal hippocampus of TgCRND8 mice, including 1) biochemistry (CREB activation), 2) neuronal structure, and 3) neuronal network activity. Moreover, locally and acutely increasing CREB function in the CA1 region of TgCRND8 mice was sufficient to restore function in each domain independent of plaque load or aggregated Aβ levels. Together, these studies indicate that targeting GluA2 or CREB may be useful therapeutic strategies in treating AD.

Alzheimer’s disease (AD), a neurodegenerative disorder initially characterized by mild memory impairments, progresses to global cognitive deficits and eventually death. AD pathological hallmarks are plaques and tangles. Acute and chronic effects of familial Alzheimer’s disease (FAD) genes were examined in WT and transgenic mice respectively. We used viral vectors to acutely express FAD genes encoding the Swedish, Indiana, and Swedish and Indiana double mutation, of amyloid precursor protein (APP) in the hippocampal CA1 region (which exhibits early AD pathology) in mice. Acute expression of FAD genes produced deficits in the formation but not retreival of spatial memory. We next examined spine density as changes are thought to affect synaptic plasticity. Acute expression of FAD genes did not affect the structure (dendritic length, intersections and nodes), but decreased spine density in infected CA1 neurons. Amyloid beta (Aβ) binds to excitatory synapses, particularly to GluA2-AMPA receptors (AMPAR) leading to endocytosis. Therefore,, acute CA1 expression of FAD genes produced spatial memory formation deficits mediated by impairments in dendritic spine plasticity and transmission via AMPAR endocytosis. Additionally, infusing GluA2-3Y, a peptide that prevents Aβ induced AMPAR endocytosis in acute and chronic (TgCRND8) AD mouse models expressing double mutated APP genes, was similarly able to rescue the spatial memory and spine density deficits. Since the transcription factor CREB is critical for normal memory formation across species, we investigated its role in TgCRND8 mice. We observed additional deficits in the dorsal hippocampus of TgCRND8 mice, including 1) biochemistry (CREB activation), 2) neuronal structure, and 3) neuronal network activity. Moreover, locally and acutely increasing CREB function in the CA1 region of TgCRND8 mice was sufficient to restore function in each domain independent of plaque load or aggregated Aβ levels. Together, these studies indicate that targeting GluA2 or CREB may be useful therapeutic strategies in treating AD.

Alzheimer’s disease (AD) is a neurologically debilitating disease that is plaguing our elderly population. Transgenic mice with Alzheimer’s disease mutations are used to study signal pathways, potential drug targets and mechanism of disease. However, studies of the effects of different AD mutations on behavior and neuropathological progression in mice have been inconsistent when comparing different genetic backgrounds. The aim of this study was to compare two commonly used TgCRND8 backgrounds, the 129SvEvtac/C57F1 and C3H/C57F1 strains, for memory function in the Morris water maze (MWM), and to determine differences in plaque burden. We found deficits in multiple parameters of the MWM in the 129SvEvtac/C57F1 strain. Similarly, this background strain showed significantly more amyloid beta (Aβ) plaque burden than the C3H/C57F1 strain. This supports the hypothesis that strain specific differences are apparent in spatial memory testing and neuropathologic progression of AD. It leads us to believe that epigenetics are key to understanding AD risk assessment and development.

No description available.

No description available.

No description available.