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Isolation of CDNA encoding a novel protein that associates with neuron-specific X11L protein
Poster
Presentation:
Clinical
Poster Presentation:
Research
Clinical
I
Research
S23
I
ISOLATION OF CDNA ENCODING A NOVEL PROTEIN THAT ASSOCIATES WITH NEURON-SPECIFIC XIII, PROTEIN.
CLINICAL AND NEUROPSYCHOLOGICAL CORRELATES OF IMPAIRED AWARENESS OF DEFICITS IN ALZHEIMER’S DISEASE (AD) AND PARKINSON’S DISEASE (PD): A COMPARATIVE STUDY
Unawareness of deficits in AD has been studied in relation to disease vartables and symptoms, but has rarely been correlated with other, potentially localizable, domain\ of neuropsychological function. Nor hx unawareness been examined systematically in other dementia. Awareness of deficits in cognitive, beIf-care, social interaction, and motor functions were measured in 30 subjects with AD and 32 with PD by computing discrepancy scores between patients’ self-ratings and those of their caregivers on subscales derived from the Patient Competency Rating Scale (PCRS) (Prigatano) and the Unified PD Rating Scale (UPDRS). These “dircrepancy scores” were first compared between diagnostic groups and then correlated with total and wbscale scores on the Dementia Rating Scale (DRS) (Mattis) and other clinical variables, including age at onset. duration of disease, clinical dementia rating (CDR), Cornell depression, and Mm-mental state (MMS) scores. Covarying for education. age, duration and MMS scores, as a group, AD patients were significantly more unaware than PD patients.of cognitive deficits as measured by the PCRS (p=.O28). but did not differ in awareness of problems in other domains. When PD patients were divided into those with (MMSs25) and without (MMSz26) dementia. demented PD patients showed significantly more unawareness of cognitive (p=.O17), self-care (p=.006),and social interaction (p=.O22) deficits on the PCRS as well as motor dirabihty (p=.O3X). than the nondemented. Viewed across functional domains, in AD, unawareness was most frequently associated with more severe dementia, aa measured by CDR. and lower scores on the Intttation/perseveration subscale of the DRS (p’si.05); in PD unawareness was most frequently assoaated with more evere dementia, as measured by CDR and MMS, and lower scores in the DRS Memory subscale (p‘s<.O5). Thus, unawarenear of selected deficm occur\ in AD and in PD wth dementia. Although associated with dementia severity in both groups, specific neuropsychologic correlates of awareneu in the twn diagnostic conditrioe differ. raising the question of different mechanisms underlying the phenomenon
THE ROLE OF T CELL REACTIVITY TO A-BETA AMYLOID PEPTIDE IN THE PATHOGENIC PROCESSES ASSOCIATED WITH ALZHEIMER’S DISEASE.
The pathology of Alzheimer disease (AD) is assouated with the depositton of totrigger a neurotoxic cascade. The amyloid p- protein (Ap) in the brain that appears APplaques formed in the brain are also associated with CNS inflammatory responses that may enhance the toxic environment of neurons. However, the immunogenicity of APwith regard to the activation of AP-speafic T cells and their role in the pathology of the disease is not well understood. We investigated T cell reactivity to Apl-40 and ApI-42, the major peptidea that aggregate and lead to Abplaque formation. We found that in C57B16 mice T cell lines generated to either API-40 or API-42 antigen are responsive to both API-40 and Api-42. and that the dominant yite for T cell acttvation is between amino acids 15-30. Interestingly, a fibrillu form of AP, known to be toxic to neurons in vitro, appears to enhance T cell activation as comp?red with the roluble form of the peptide. We also found that the B7.2 costimulatory molecule. a second signal for T cell activation, ia expressed m the brain of mice transgenic for amyloid precursor protem (APP) m association with plaque formation and local activation of astrocytes and microglia. In initial human studies, we were able to identify CD4+ and CD8+ A@reactive T cells in the peripheral blood. Interestingly, marked reactivity was observed in T cells from several of the older individuals tested. Moreover API-42, which is more closely linked to the initiation of neuropathology of AD, dominantly Induced secondary T cell activation in vitro as compared with API-40. Thus, it is possible that A@utoreacttve T cells may be activated during the course of Aodeposition in the brain and depending on their phenotype and state of activation could have positive or negative effects on A@-related neuropathology.
Xl l-like (XI IL) protem was originally isolated as a protein that interacts with the cytoplasmic domain of amyloid precursor protein (APP). XI IL has 53.5% amino acid homology to Xl I protein. Both proteins contain a middle phosphotyrosine (PI) interaction domain and carboxyl-terminal two PDZ domains. However, the conservation of the amino-terminal domain between the both proteins is comparatively low (18.3%). The amino-terminal domain has a pocribihty to regulate the binding specificity of Xl IL to other protems including APP. Therefore. we isolated and characterired proteins that interact with the amino-terminal domam of Xl IL. One of them. a novel protein XB51 interferes with the association of Xl IL with APP. Association XB51 with Xl IL alteres the intracellular localization of XB5 I. Furthermore. XB5l interacts with other proteins strongly in neuronal cells and this interaction I\ interfered in part by exprecsmn of Xl IL. These intracellular protetn mtrraction composed of APP, XI IL, XB5 I and XB5 I asaociattng proteins may ploy an mportant role in the pathogetwsts of Alrheimer‘s disease.
PHENOTYPIC ALTERATIONS TRIGGERED BY A NOVEL MUTATION RESPONSIBLE FOR EARLY ONSET ALZHEIMER’S DISEASE: A STUDY ON BAPP MATURATION AND APOPTOTIC RESPONSE
We have identified a novel pAPP mutation (V715M-PAPP770) which cnegregata with early onset Alzheimer’a disease (AD) in il pedigree. Unlike other Familial AD (FAD)-linked pAPP mutations reported to date, overexprewon of V7 ISM-@APP in human HEK293 cells and murine neurons reduces total Abproduction and increases the recwery of the phy?iolagicaily secreted product, APPa. V715M-PAPP aignificantly reducea AP40 secretion without affecting AP42 production in HEK293 cell\. However. a marked increase in N-terminally-truncated APending at position 42 (x-42AP) is observed, while its counterpart x-40Apts not affected. This unusual phenotypic alteration of the pAPP maturation could be due to either altered kinetic\ parameters of secretases triggered by mutated residues or related to a misrouting of pAPP to a cell compatment displaying distinct becretase~ content. In order to furthrl cxamine these two possibilities, we have studied the processing of the 99 ammo-acids C99-terminal P-wxtase-derived fragment of BAPP in which the V715M mutation was introduced. This V715MCY9 construction was compared to C99 construction\ bearing the Florida and London mutations only, or in association with V715M. Our data support the hypothesis of a direct influence of the V715M mutation on u-secretases activities. Overall. our results uggat that in some case\. FAD may be nwxiated wth a reduction in the production of ADbut may be caused by mcreased production of truncated forms of APending at the 42 position. Here, we alao describe the influence of the novel muattion on the apoptotic rrsponae of human cells.
Presentation:
Clinical
Poster Presentation:
Research
Clinical
I
Research
S23
I
ISOLATION OF CDNA ENCODING A NOVEL PROTEIN THAT ASSOCIATES WITH NEURON-SPECIFIC XIII, PROTEIN.
CLINICAL AND NEUROPSYCHOLOGICAL CORRELATES OF IMPAIRED AWARENESS OF DEFICITS IN ALZHEIMER’S DISEASE (AD) AND PARKINSON’S DISEASE (PD): A COMPARATIVE STUDY
Unawareness of deficits in AD has been studied in relation to disease vartables and symptoms, but has rarely been correlated with other, potentially localizable, domain\ of neuropsychological function. Nor hx unawareness been examined systematically in other dementia. Awareness of deficits in cognitive, beIf-care, social interaction, and motor functions were measured in 30 subjects with AD and 32 with PD by computing discrepancy scores between patients’ self-ratings and those of their caregivers on subscales derived from the Patient Competency Rating Scale (PCRS) (Prigatano) and the Unified PD Rating Scale (UPDRS). These “dircrepancy scores” were first compared between diagnostic groups and then correlated with total and wbscale scores on the Dementia Rating Scale (DRS) (Mattis) and other clinical variables, including age at onset. duration of disease, clinical dementia rating (CDR), Cornell depression, and Mm-mental state (MMS) scores. Covarying for education. age, duration and MMS scores, as a group, AD patients were significantly more unaware than PD patients.of cognitive deficits as measured by the PCRS (p=.O28). but did not differ in awareness of problems in other domains. When PD patients were divided into those with (MMSs25) and without (MMSz26) dementia. demented PD patients showed significantly more unawareness of cognitive (p=.O17), self-care (p=.006),and social interaction (p=.O22) deficits on the PCRS as well as motor dirabihty (p=.O3X). than the nondemented. Viewed across functional domains, in AD, unawareness was most frequently associated with more severe dementia, aa measured by CDR. and lower scores on the Intttation/perseveration subscale of the DRS (p’si.05); in PD unawareness was most frequently assoaated with more evere dementia, as measured by CDR and MMS, and lower scores in the DRS Memory subscale (p‘s<.O5). Thus, unawarenear of selected deficm occur\ in AD and in PD wth dementia. Although associated with dementia severity in both groups, specific neuropsychologic correlates of awareneu in the twn diagnostic conditrioe differ. raising the question of different mechanisms underlying the phenomenon
THE ROLE OF T CELL REACTIVITY TO A-BETA AMYLOID PEPTIDE IN THE PATHOGENIC PROCESSES ASSOCIATED WITH ALZHEIMER’S DISEASE.
The pathology of Alzheimer disease (AD) is assouated with the depositton of totrigger a neurotoxic cascade. The amyloid p- protein (Ap) in the brain that appears APplaques formed in the brain are also associated with CNS inflammatory responses that may enhance the toxic environment of neurons. However, the immunogenicity of APwith regard to the activation of AP-speafic T cells and their role in the pathology of the disease is not well understood. We investigated T cell reactivity to Apl-40 and ApI-42, the major peptidea that aggregate and lead to Abplaque formation. We found that in C57B16 mice T cell lines generated to either API-40 or API-42 antigen are responsive to both API-40 and Api-42. and that the dominant yite for T cell acttvation is between amino acids 15-30. Interestingly, a fibrillu form of AP, known to be toxic to neurons in vitro, appears to enhance T cell activation as comp?red with the roluble form of the peptide. We also found that the B7.2 costimulatory molecule. a second signal for T cell activation, ia expressed m the brain of mice transgenic for amyloid precursor protem (APP) m association with plaque formation and local activation of astrocytes and microglia. In initial human studies, we were able to identify CD4+ and CD8+ A@reactive T cells in the peripheral blood. Interestingly, marked reactivity was observed in T cells from several of the older individuals tested. Moreover API-42, which is more closely linked to the initiation of neuropathology of AD, dominantly Induced secondary T cell activation in vitro as compared with API-40. Thus, it is possible that A@utoreacttve T cells may be activated during the course of Aodeposition in the brain and depending on their phenotype and state of activation could have positive or negative effects on A@-related neuropathology.
Xl l-like (XI IL) protem was originally isolated as a protein that interacts with the cytoplasmic domain of amyloid precursor protein (APP). XI IL has 53.5% amino acid homology to Xl I protein. Both proteins contain a middle phosphotyrosine (PI) interaction domain and carboxyl-terminal two PDZ domains. However, the conservation of the amino-terminal domain between the both proteins is comparatively low (18.3%). The amino-terminal domain has a pocribihty to regulate the binding specificity of Xl IL to other protems including APP. Therefore. we isolated and characterired proteins that interact with the amino-terminal domam of Xl IL. One of them. a novel protein XB51 interferes with the association of Xl IL with APP. Association XB51 with Xl IL alteres the intracellular localization of XB5 I. Furthermore. XB5l interacts with other proteins strongly in neuronal cells and this interaction I\ interfered in part by exprecsmn of Xl IL. These intracellular protetn mtrraction composed of APP, XI IL, XB5 I and XB5 I asaociattng proteins may ploy an mportant role in the pathogetwsts of Alrheimer‘s disease.
PHENOTYPIC ALTERATIONS TRIGGERED BY A NOVEL MUTATION RESPONSIBLE FOR EARLY ONSET ALZHEIMER’S DISEASE: A STUDY ON BAPP MATURATION AND APOPTOTIC RESPONSE
We have identified a novel pAPP mutation (V715M-PAPP770) which cnegregata with early onset Alzheimer’a disease (AD) in il pedigree. Unlike other Familial AD (FAD)-linked pAPP mutations reported to date, overexprewon of V7 ISM-@APP in human HEK293 cells and murine neurons reduces total Abproduction and increases the recwery of the phy?iolagicaily secreted product, APPa. V715M-PAPP aignificantly reducea AP40 secretion without affecting AP42 production in HEK293 cell\. However. a marked increase in N-terminally-truncated APending at position 42 (x-42AP) is observed, while its counterpart x-40Apts not affected. This unusual phenotypic alteration of the pAPP maturation could be due to either altered kinetic\ parameters of secretases triggered by mutated residues or related to a misrouting of pAPP to a cell compatment displaying distinct becretase~ content. In order to furthrl cxamine these two possibilities, we have studied the processing of the 99 ammo-acids C99-terminal P-wxtase-derived fragment of BAPP in which the V715M mutation was introduced. This V715MCY9 construction was compared to C99 construction\ bearing the Florida and London mutations only, or in association with V715M. Our data support the hypothesis of a direct influence of the V715M mutation on u-secretases activities. Overall. our results uggat that in some case\. FAD may be nwxiated wth a reduction in the production of ADbut may be caused by mcreased production of truncated forms of APending at the 42 position. Here, we alao describe the influence of the novel muattion on the apoptotic rrsponae of human cells.