- Email: [email protected]
PL-03-02: Dissecting the function of APP by the characterization of APP-interacting proteins
Symposia S3-01: Other Dementias Consortium efforts are likely to generate the necessary sample sizes to both identify and confirm new LOAD loci. PL-03-02
DISSECTING THE FUNCTION OF APP BY THE CHARACTERIZATION OF APP-INTERACTING PROTEINS
tion of NF-kB signaling in microglia, and is followed by the accumulation of intraneuronal A in the hippocampus. Conclusions: The extent to which the different pathological effects of apoE4 are mediated by parallel and/or converging mechanisms will be discussed. TUESDAY, JULY 29, 2008 SYMPOSIA S3-01 OTHER DEMENTIAS
Joseph D. Buxbaum, Mount Sinai School of Medicine, New York, NY, USA. Contact e-mail: [email protected] Background: Since its discovery over 20 years ago, a detailed understanding of the function of the Azheimer amyloid protein precursor (APP) has remained elusive. Methods: One important means by which we can understand the function of APP is by identifying proteins that interact with it. Results: The APP cytoplasmic domain is highly conserved across all species studied, consistent with an important functional role for this domain. Similarly, in the extracellular domain of APP, there are two conserved regions, with likely important functional roles. Multiple groups have carried out yeast two-hybrid and additional analysis with the APP cytoplasmic domains and identified important interacting proteins including FE65 and X11 proteins. The discovery of FE65 in turn led to the identification of a transcriptional role for APP. Although the genes targeted by this pathway remain to be fully elucidated, we know of several, which in turn provide important data on functions of APP. Similarly, studies of X11 and of additional APPbinding proteins support a role for APP in key cell biological processes. Conclusions: In this talk, we will review the data for APP-binding proteins and discuss what this suggests about the potential functional roles for APP. PL-03-03
APOLIPOPROTEIN E4: THE MOST PREVALENT YET UNDERSTUDIED GENETIC RISK FACTOR OF ALZHEIMER’S DISEASE
Daniel Michaelson, Tel-Aviv University, Tel-Aviv, Israel. Contact email: [email protected] Background: The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor of Alzheimer’s disease (AD), decreases the age of onset of the disease in a gene dose-dependent manner. Histopathologically, apoE4 is associated with elevated levels of brain amyloid- (A) deposits and brain inflammation, with impaired neuronal plasticity, and with increased susceptibility to brain insults. In spite of the strong and incontrovertible impact of apoE4 in AD, it is understudied and the mechanisms underlying its pathological effects are poorly understood. Several nonmutually exclusive theories have been proposed. These include cross talk interactions with A, impairments in apoE receptor-mediated signaling and transport processes, hyper activation of microglia, and isoform-specific degradation of apoE4 to neurotoxic fragments. Methods: We will presently employ apoE4 transgenic mice and distinct paradigms that specifically induce the expression of the different pathological phenotypes of apoE4, for studying the cellular and molecular mechanisms that underlie these effects. Results: Activation of the amyloid cascade by inhibition of the A-degrading enzyme neprilysin revealed that apoE4 isoform-specifically stimulates the degeneration of hippocampal entorhinal and septal neurons, which is accompanied by the accumulation of intracellular A and apoE as well as the activation of lysosomes. Furthermore, these neuropathological effects are associated isoform-specifically with the occurrence of pronounced cognitive deficits in the ApoE4 mice. Neuronal plasticity experiments revealed that apoE4 inhibits synaptogenesis and neurogenesis and stimulates apoptosis in hippocampal neurons of apoE4 mice that have been exposed to an enriched environment. These effects are also associated with the specific accumulation of intracellular A and apoE4 in the affected neurons, suggesting that the impairments in neuronal plasticity caused by apoE4 are mediated by A. Induction of acute and chronic brain inflammation revealed that apoE4 up-regulates the expression of inflammation-related genes. This effect is related to hyper activa-
T149
S3-01-01
FTD GENETICS AND PROGRANULIN
Mike Hutton, Mayo Clinic College of Medicine, Jacksonville, FL, USA. Contact e-mail: [email protected] Abstract not available. S3-01-02
TDP-43 PROTEINOPATHIES
Ian Mackenzie, Vancouver General Hospital, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada. Contact e-mail: [email protected] Background: The TAR DNA binding protein TDP-43 is a nuclear protein expressed in various tissues, with functions that include transcription repression and activation of exon skipping. The physiological role of TDP-43 in the brain is currently unknown, however it is normally localized to the nucleus of neurons and some glia. The recent identification of abnormal TDP-43 as the major pathological protein in the most common subtype of frontotemporal lobar degeneration (FTLD with ubiquitinated inclusions, FTLD-U) and in ALS represents a major breakthrough in understanding the pathogenesis and inter-relationship of these conditions. Defining the clinical and pathological spectrum of this new biochemical class of neurodegenerative disease is the focus of ongoing research. Methods: Literature review. Results: Each of the known genetic causes of familial FTLD-U is associated with a characteristic pattern of neuropathology and in most (including mutations in PGRN, VCP and linked to chromosome 9p) the pathology is TDP-43-positive. The one exception is FTD linked to chromosome 3, caused by a CHMP2B mutation, which has neuronal inclusions that are ubiquitinated but not reactive for TDP-43. The vast majority of sporadic FTLD-U cases also have TDP-43 pathology, however there exists a small proportion that are TDP-43-negative. These cases of “atypical” FTLD-U have a highly consistent clinical phenotype, unique neuropathology and probably represent a discrete entity. In ALS, all sporadic and familial cases without SOD1 mutations have TDP-43-positive inclusions in both motor neurons and glia; however, cases with SOD1 mutations have no evidence of pathological TDP-43. An important recent development has been the identification of TDP-43 mutations in some familial ALS. TDP-43 pathology may also coexist in a variety of other neurodegenerative conditions, including hippocampal sclerosis, ALS-parkinsonism-dementia complex of Guam, Pick’s disease and a significant proportion of Alzheimer’s and Lewy body disease. The specific role of TDP-43 in neurodegeneration remains speculative, however, possibilities include loss of some essential nuclear function or disruption of crucial intracellular processes by the accumulation of insoluble, mis-folded protein. Conclusions: The TDP-43 proteinopathies represent an important new class of neurodegenerative disease. Defining the biochemical basis of these conditions will facilitate the development of useful biomarkers and therapies. S3-01-03
PRION THERAPY: TETRACYCLIC COMPOUNDS IN ANIMAL MODELS AND PATIENTS WITH CREUTZFELDT-JAKOB DISEASE
Fabrizio Tagliavini, Instituto Nazionale Neurologico, Milano, Italy. Contact e-mail: [email protected] Background: The prion diseases are fatal neurodegenerative disorders for which no effective treatment is available. A large number of molecules
DISSECTING THE FUNCTION OF APP BY THE CHARACTERIZATION OF APP-INTERACTING PROTEINS
tion of NF-kB signaling in microglia, and is followed by the accumulation of intraneuronal A in the hippocampus. Conclusions: The extent to which the different pathological effects of apoE4 are mediated by parallel and/or converging mechanisms will be discussed. TUESDAY, JULY 29, 2008 SYMPOSIA S3-01 OTHER DEMENTIAS
Joseph D. Buxbaum, Mount Sinai School of Medicine, New York, NY, USA. Contact e-mail: [email protected] Background: Since its discovery over 20 years ago, a detailed understanding of the function of the Azheimer amyloid protein precursor (APP) has remained elusive. Methods: One important means by which we can understand the function of APP is by identifying proteins that interact with it. Results: The APP cytoplasmic domain is highly conserved across all species studied, consistent with an important functional role for this domain. Similarly, in the extracellular domain of APP, there are two conserved regions, with likely important functional roles. Multiple groups have carried out yeast two-hybrid and additional analysis with the APP cytoplasmic domains and identified important interacting proteins including FE65 and X11 proteins. The discovery of FE65 in turn led to the identification of a transcriptional role for APP. Although the genes targeted by this pathway remain to be fully elucidated, we know of several, which in turn provide important data on functions of APP. Similarly, studies of X11 and of additional APPbinding proteins support a role for APP in key cell biological processes. Conclusions: In this talk, we will review the data for APP-binding proteins and discuss what this suggests about the potential functional roles for APP. PL-03-03
APOLIPOPROTEIN E4: THE MOST PREVALENT YET UNDERSTUDIED GENETIC RISK FACTOR OF ALZHEIMER’S DISEASE
Daniel Michaelson, Tel-Aviv University, Tel-Aviv, Israel. Contact email: [email protected] Background: The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor of Alzheimer’s disease (AD), decreases the age of onset of the disease in a gene dose-dependent manner. Histopathologically, apoE4 is associated with elevated levels of brain amyloid- (A) deposits and brain inflammation, with impaired neuronal plasticity, and with increased susceptibility to brain insults. In spite of the strong and incontrovertible impact of apoE4 in AD, it is understudied and the mechanisms underlying its pathological effects are poorly understood. Several nonmutually exclusive theories have been proposed. These include cross talk interactions with A, impairments in apoE receptor-mediated signaling and transport processes, hyper activation of microglia, and isoform-specific degradation of apoE4 to neurotoxic fragments. Methods: We will presently employ apoE4 transgenic mice and distinct paradigms that specifically induce the expression of the different pathological phenotypes of apoE4, for studying the cellular and molecular mechanisms that underlie these effects. Results: Activation of the amyloid cascade by inhibition of the A-degrading enzyme neprilysin revealed that apoE4 isoform-specifically stimulates the degeneration of hippocampal entorhinal and septal neurons, which is accompanied by the accumulation of intracellular A and apoE as well as the activation of lysosomes. Furthermore, these neuropathological effects are associated isoform-specifically with the occurrence of pronounced cognitive deficits in the ApoE4 mice. Neuronal plasticity experiments revealed that apoE4 inhibits synaptogenesis and neurogenesis and stimulates apoptosis in hippocampal neurons of apoE4 mice that have been exposed to an enriched environment. These effects are also associated with the specific accumulation of intracellular A and apoE4 in the affected neurons, suggesting that the impairments in neuronal plasticity caused by apoE4 are mediated by A. Induction of acute and chronic brain inflammation revealed that apoE4 up-regulates the expression of inflammation-related genes. This effect is related to hyper activa-
T149
S3-01-01
FTD GENETICS AND PROGRANULIN
Mike Hutton, Mayo Clinic College of Medicine, Jacksonville, FL, USA. Contact e-mail: [email protected] Abstract not available. S3-01-02
TDP-43 PROTEINOPATHIES
Ian Mackenzie, Vancouver General Hospital, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada. Contact e-mail: [email protected] Background: The TAR DNA binding protein TDP-43 is a nuclear protein expressed in various tissues, with functions that include transcription repression and activation of exon skipping. The physiological role of TDP-43 in the brain is currently unknown, however it is normally localized to the nucleus of neurons and some glia. The recent identification of abnormal TDP-43 as the major pathological protein in the most common subtype of frontotemporal lobar degeneration (FTLD with ubiquitinated inclusions, FTLD-U) and in ALS represents a major breakthrough in understanding the pathogenesis and inter-relationship of these conditions. Defining the clinical and pathological spectrum of this new biochemical class of neurodegenerative disease is the focus of ongoing research. Methods: Literature review. Results: Each of the known genetic causes of familial FTLD-U is associated with a characteristic pattern of neuropathology and in most (including mutations in PGRN, VCP and linked to chromosome 9p) the pathology is TDP-43-positive. The one exception is FTD linked to chromosome 3, caused by a CHMP2B mutation, which has neuronal inclusions that are ubiquitinated but not reactive for TDP-43. The vast majority of sporadic FTLD-U cases also have TDP-43 pathology, however there exists a small proportion that are TDP-43-negative. These cases of “atypical” FTLD-U have a highly consistent clinical phenotype, unique neuropathology and probably represent a discrete entity. In ALS, all sporadic and familial cases without SOD1 mutations have TDP-43-positive inclusions in both motor neurons and glia; however, cases with SOD1 mutations have no evidence of pathological TDP-43. An important recent development has been the identification of TDP-43 mutations in some familial ALS. TDP-43 pathology may also coexist in a variety of other neurodegenerative conditions, including hippocampal sclerosis, ALS-parkinsonism-dementia complex of Guam, Pick’s disease and a significant proportion of Alzheimer’s and Lewy body disease. The specific role of TDP-43 in neurodegeneration remains speculative, however, possibilities include loss of some essential nuclear function or disruption of crucial intracellular processes by the accumulation of insoluble, mis-folded protein. Conclusions: The TDP-43 proteinopathies represent an important new class of neurodegenerative disease. Defining the biochemical basis of these conditions will facilitate the development of useful biomarkers and therapies. S3-01-03
PRION THERAPY: TETRACYCLIC COMPOUNDS IN ANIMAL MODELS AND PATIENTS WITH CREUTZFELDT-JAKOB DISEASE
Fabrizio Tagliavini, Instituto Nazionale Neurologico, Milano, Italy. Contact e-mail: [email protected] Background: The prion diseases are fatal neurodegenerative disorders for which no effective treatment is available. A large number of molecules