- Email: [email protected]
Patterns of brain atrophy in frontotemporal dementia with mutations in MAPT or PGRN
Poster Presentations P3 5 Division of Neurology, Duke University, Durham, NC, USA; 6Centro de Investigacio´n Biome´dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. Contact e-mail: [email protected]
Background: It has been proposed that deregulation of neuronal glycogen synthase kinase 3 (GSK3) activity, may be a key feature in Alzheimer disease pathogenesis. We have previously generated transgenic mice that conditionally overexpress GSK3b, mainly in dentate gyrus (DG), a region involved in learning and memory acquisition. We have found that a consequence of GSK3 overexpression was DG degeneration. Methods: To study whether pathology induced by GSK3b overexpression could be the consequence of the appearance of hyperphosphorylated tau, or if the modification of other GSK3 sustrates may play a more important role in that pathology, we have isolated a genetic modified mice lacking tau protein and overexpressing GSK3b. The triple transgenic mice, Tet/GSK3b/tau-/-, were generated by crossing mice expressing Tet/GSK3b and tau knockout mice. Tet/GSK3b/tau-/- mice gene expression, as well as that of its controls (wild type, tau-/- and Tet/ GSK3b), was confirmed. Cognitive function of 3 month-old Tet/GSK3b/ tau-/- mice and wild type, tau-/- and Tet/GSK3b littermates was determined in the Morris water maze. Thionine-stained brain sections, from each type of mice were analyzed in 3 and 18 months old mice to measure the DG volume. We performed immunohistochemistry with GFAP and IBA-1 antibodies to analyze reactive gliosis in the hippocampus. Results: Tet/ GSK3b/tau-/- mice showed behavioural deficit in the Morris water maze, compared to wild type and tau-/- mice, but it performed the task better than Tet/GSK3b mice. This result correlates with the lower DG atrophy observed in the Tet/GSK3b/tau-/- mice compared to Tet/GSK3b. This degeneration in the hippocampus of Tet/GSK3b/tau-/- mice was accompanied by reactive gliosis. We analyzed bcatenin levels in nucleus and cytoplasm of hippocampal neurons and we observed a reduction in bcatenin level in the nuclear fraction of Tet/GSK3b and Tet/GSK3b/tau-/- compared to wild type or tau-/littermates, although the nuclear bcatenin level for Tet/GSK3b/tau-/- was even slightly lower than that of Tet/GSK3 mice. Conclusions: Our results indicate that the toxic effect of GSK3 overexpression is milder in the absence of tau. Thus, we suggest that the presence of phosphotau could mediate, at least in part, the pathology observed by overexpression of GSK3 in mouse brain. P3-211
AMYLOID BETA: A PUTATIVE INTRASPINAL MICROTUBULE-DEPOLYMERIZER TO INDUCE SYNAPSE LOSS OR SPINAL SHORTENING IN ALZHEIMER’S DISEASE
Fuyuki Mitsuyama, Fujita-Health University, Toyoake, Aichi, Japan. Contact e-mail: [email protected] Background: A loss or shortening of dendritic spines has been described in patients with neurodegenerative disorders such as Alzheimer’s disease (AD), and in mouse models for these disorders. Such alteration is thought to be responsible for cognitive deficits long before or even in the absence of neuronal loss, but the underlying mechanisms are poorly understood. Methods: We studied by light- and electron-microscopy the distribution of microtubules in dendrites of CA1 neurons of non-stimulated and stimulated rat hippocampal slices after very strong tetanic stimulation for inducing long-term potentiation. Results: As a result, we observed the following changes: 1. In immunofluorescence for microtubules and IP3 receptor using ultrathin-cryosections, linear signals of microtubules in main dendritic shafts were changed into fragmented. 2. Many spotty signals of microtubules emerged at the peripheral area of dendrites. Electron-microscopically, there was redistribution of microtubules in dendritic spines and dendritic shafts, and the thickening of post-synaptic density. 3. Many microtubules concentrated to thickened postsynaptic density in spines and new ones emerged, going to spines from dendritic shafts. Conclusions: This means that the nucleus is connected only with simulated postsynaptic membranes by microtubules. This newly produced microtubule track only to the stimulated postsynaptic membrane might be the route of the bi-directional transportation of signals during LTP formation. This lead us the hypothesis of the ‘‘endless memory amplifying circuit’’ that means gene expression-promoting molecules are translocated from postsynaptic membrane to the cell body and enter into nucleus and activate transcription factors, and gene products, which will probably promote plasticity,
P405
may be re-translocated only to the stimulated postsynaptic membrane along microtubules. From our experimental results, to maintain the newly produced microtubules in dendritic spines may be essential to form memory, and the dendritic spines may be enlarged by the pushing force of microtubules to the postsynaptic membranes as a tent pole, which are polymerized by the postsynaptic stimulation. So, our experimental results strongly suggest that amyloid beta may induce a loss or shortening of dendritic spines via depolymerization of microtubules in the dendritic spines, resulting in the disruption of the endless memory amplifying circuit, and finally cognitive deficits. P3-212
PATTERNS OF BRAIN ATROPHY IN FRONTOTEMPORAL DEMENTIA WITH MUTATIONS IN MAPT OR PGRN
Jennifer L. Whitwell1, Clifford R. Jack, Jr1, Bradley F. Boeve1, Matthew L. Senjem1, Rosa Rademakers2, Matthew Baker2, Robert J. Ivnik1, David S. Knopman1, Zbigniew W. Wszolek2, Ronald C. Petersen1, Keith A. Josephs1, 1Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic, Jacksonville, FL, USA. Contact e-mail: [email protected] Background: Approximately 40% of subjects with frontotemporal dementia have a positive family history with an autosomal dominant pattern of inheritance. The two most commonly mutated genes in frontotemporal dementia are microtubule associated protein tau (MAPT) and progranulin (PGRN), both located on chromosome 17q21. The objectives of this study were first to compare patterns of grey matter loss in subjects with mutations in PGRN to subjects with mutations in MAPT, and secondly to assess patterns of atrophy in different MAPT mutations. Methods: We identified 12 subjects with a mutation in PGRN and 19 subjects with a mutation in MAPT that had volumetric MRI. In order to compare the PGRN and MAPT groups we selected 12 of the MAPT subjects, matched by time from disease onset-toscan to the PGRN subjects. Voxel-based morphometry (VBM) was used to assess patterns of grey matter loss in these PGRN and MAPT groups compared to controls, and compared to each other. In addition, we used VBM to assess patterns of loss in groups of subjects with the IVS10þ3, IVS10þ16, S305N and N279K mutations which influence the splicing of tau RNA, and the P301L and V337M mutations that affect the structure of the tau protein. Results: Both PGRN and MAPT groups showed frontal, temporal and parietal lobe grey matter loss compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT (Figure). The MAPT subjects showed greater loss in the medial temporal lobes than the PGRN subjects. The different MAPT mutations all showed predominant anterior temporal lobe atrophy. Subjects with IVS10þ3, IVS10þ16, S305N and N279K mutations showed most significant loss in anteromedial temporal lobes, whereas subjects with P301L and V337M mutations showed most significant loss in the lateral temporal lobes (Figure). Conclusions: Patterns of atrophy on MRI differ between PGRN and MAPT mutation carriers. Furthermore, while all MAPT mutations were associated with temporal atrophy the P301L and V337M mutations showed a different pattern of temporal involvement to the IVS10þ3, IVS10þ16, S305N and N279K mutations. Patterns of atrophy may therefore aid in the differentiation of these different mutations.
Background: It has been proposed that deregulation of neuronal glycogen synthase kinase 3 (GSK3) activity, may be a key feature in Alzheimer disease pathogenesis. We have previously generated transgenic mice that conditionally overexpress GSK3b, mainly in dentate gyrus (DG), a region involved in learning and memory acquisition. We have found that a consequence of GSK3 overexpression was DG degeneration. Methods: To study whether pathology induced by GSK3b overexpression could be the consequence of the appearance of hyperphosphorylated tau, or if the modification of other GSK3 sustrates may play a more important role in that pathology, we have isolated a genetic modified mice lacking tau protein and overexpressing GSK3b. The triple transgenic mice, Tet/GSK3b/tau-/-, were generated by crossing mice expressing Tet/GSK3b and tau knockout mice. Tet/GSK3b/tau-/- mice gene expression, as well as that of its controls (wild type, tau-/- and Tet/ GSK3b), was confirmed. Cognitive function of 3 month-old Tet/GSK3b/ tau-/- mice and wild type, tau-/- and Tet/GSK3b littermates was determined in the Morris water maze. Thionine-stained brain sections, from each type of mice were analyzed in 3 and 18 months old mice to measure the DG volume. We performed immunohistochemistry with GFAP and IBA-1 antibodies to analyze reactive gliosis in the hippocampus. Results: Tet/ GSK3b/tau-/- mice showed behavioural deficit in the Morris water maze, compared to wild type and tau-/- mice, but it performed the task better than Tet/GSK3b mice. This result correlates with the lower DG atrophy observed in the Tet/GSK3b/tau-/- mice compared to Tet/GSK3b. This degeneration in the hippocampus of Tet/GSK3b/tau-/- mice was accompanied by reactive gliosis. We analyzed bcatenin levels in nucleus and cytoplasm of hippocampal neurons and we observed a reduction in bcatenin level in the nuclear fraction of Tet/GSK3b and Tet/GSK3b/tau-/- compared to wild type or tau-/littermates, although the nuclear bcatenin level for Tet/GSK3b/tau-/- was even slightly lower than that of Tet/GSK3 mice. Conclusions: Our results indicate that the toxic effect of GSK3 overexpression is milder in the absence of tau. Thus, we suggest that the presence of phosphotau could mediate, at least in part, the pathology observed by overexpression of GSK3 in mouse brain. P3-211
AMYLOID BETA: A PUTATIVE INTRASPINAL MICROTUBULE-DEPOLYMERIZER TO INDUCE SYNAPSE LOSS OR SPINAL SHORTENING IN ALZHEIMER’S DISEASE
Fuyuki Mitsuyama, Fujita-Health University, Toyoake, Aichi, Japan. Contact e-mail: [email protected] Background: A loss or shortening of dendritic spines has been described in patients with neurodegenerative disorders such as Alzheimer’s disease (AD), and in mouse models for these disorders. Such alteration is thought to be responsible for cognitive deficits long before or even in the absence of neuronal loss, but the underlying mechanisms are poorly understood. Methods: We studied by light- and electron-microscopy the distribution of microtubules in dendrites of CA1 neurons of non-stimulated and stimulated rat hippocampal slices after very strong tetanic stimulation for inducing long-term potentiation. Results: As a result, we observed the following changes: 1. In immunofluorescence for microtubules and IP3 receptor using ultrathin-cryosections, linear signals of microtubules in main dendritic shafts were changed into fragmented. 2. Many spotty signals of microtubules emerged at the peripheral area of dendrites. Electron-microscopically, there was redistribution of microtubules in dendritic spines and dendritic shafts, and the thickening of post-synaptic density. 3. Many microtubules concentrated to thickened postsynaptic density in spines and new ones emerged, going to spines from dendritic shafts. Conclusions: This means that the nucleus is connected only with simulated postsynaptic membranes by microtubules. This newly produced microtubule track only to the stimulated postsynaptic membrane might be the route of the bi-directional transportation of signals during LTP formation. This lead us the hypothesis of the ‘‘endless memory amplifying circuit’’ that means gene expression-promoting molecules are translocated from postsynaptic membrane to the cell body and enter into nucleus and activate transcription factors, and gene products, which will probably promote plasticity,
P405
may be re-translocated only to the stimulated postsynaptic membrane along microtubules. From our experimental results, to maintain the newly produced microtubules in dendritic spines may be essential to form memory, and the dendritic spines may be enlarged by the pushing force of microtubules to the postsynaptic membranes as a tent pole, which are polymerized by the postsynaptic stimulation. So, our experimental results strongly suggest that amyloid beta may induce a loss or shortening of dendritic spines via depolymerization of microtubules in the dendritic spines, resulting in the disruption of the endless memory amplifying circuit, and finally cognitive deficits. P3-212
PATTERNS OF BRAIN ATROPHY IN FRONTOTEMPORAL DEMENTIA WITH MUTATIONS IN MAPT OR PGRN
Jennifer L. Whitwell1, Clifford R. Jack, Jr1, Bradley F. Boeve1, Matthew L. Senjem1, Rosa Rademakers2, Matthew Baker2, Robert J. Ivnik1, David S. Knopman1, Zbigniew W. Wszolek2, Ronald C. Petersen1, Keith A. Josephs1, 1Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic, Jacksonville, FL, USA. Contact e-mail: [email protected] Background: Approximately 40% of subjects with frontotemporal dementia have a positive family history with an autosomal dominant pattern of inheritance. The two most commonly mutated genes in frontotemporal dementia are microtubule associated protein tau (MAPT) and progranulin (PGRN), both located on chromosome 17q21. The objectives of this study were first to compare patterns of grey matter loss in subjects with mutations in PGRN to subjects with mutations in MAPT, and secondly to assess patterns of atrophy in different MAPT mutations. Methods: We identified 12 subjects with a mutation in PGRN and 19 subjects with a mutation in MAPT that had volumetric MRI. In order to compare the PGRN and MAPT groups we selected 12 of the MAPT subjects, matched by time from disease onset-toscan to the PGRN subjects. Voxel-based morphometry (VBM) was used to assess patterns of grey matter loss in these PGRN and MAPT groups compared to controls, and compared to each other. In addition, we used VBM to assess patterns of loss in groups of subjects with the IVS10þ3, IVS10þ16, S305N and N279K mutations which influence the splicing of tau RNA, and the P301L and V337M mutations that affect the structure of the tau protein. Results: Both PGRN and MAPT groups showed frontal, temporal and parietal lobe grey matter loss compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT (Figure). The MAPT subjects showed greater loss in the medial temporal lobes than the PGRN subjects. The different MAPT mutations all showed predominant anterior temporal lobe atrophy. Subjects with IVS10þ3, IVS10þ16, S305N and N279K mutations showed most significant loss in anteromedial temporal lobes, whereas subjects with P301L and V337M mutations showed most significant loss in the lateral temporal lobes (Figure). Conclusions: Patterns of atrophy on MRI differ between PGRN and MAPT mutation carriers. Furthermore, while all MAPT mutations were associated with temporal atrophy the P301L and V337M mutations showed a different pattern of temporal involvement to the IVS10þ3, IVS10þ16, S305N and N279K mutations. Patterns of atrophy may therefore aid in the differentiation of these different mutations.