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Increased presence of amino-terminally-truncated Aβ-peptides in presenilin 1 early-onset familial Alzheimer disease
Sl94
Poster
iNCREASED PRESENCE OF AMINO-TERMINALLY-TRUNCATED AB-PEPTIDES IN PRESENILIN 1 EARLY-ONSET FAMILIAL ALZHEIMER DISEASE.
Extracellular amyloid plaques, predominantly compowd of a 40/42 amino acid peptide defined as amyloid P-peptide (AP), are generated through the proteolysis of the amyloid precursor protein (APP). APP, with prescnilin I (PSI) and prr\enilin 2 (PS2) are the three known proteins linked to the etiology of Inherited. autosomal dominant forlns of AD. The physiological functions and the pathological effect\ of presenilin\ in AD are, at the moment, specula~we. In search for a direct evidence of PSI influence in the formation of AD peptides we analyzed the soluble AD in brain extracts from subjecta with mutated PSI and APP gcnea. in companwn to sporadic AD cases. Immunoprecipiration ot hram extracted Ab peptldes followed by gel electrophoresis and Western Blotting revealed that the production of NH2-terminally truncated AP peptide\ mainly starting at position 11, either with or without a pyroglutamate modification in this residue, is significantly (p
lssjl
CODEPOSITION OF CYSTATIN C WITH AMYLOID-BPROTEIN IN THE BRAIN OF ALZHEIMER’S DISEASE PATIENTS
Immunohistochemical analysis of brains of patients with Alrheimer’? disease and of patients with hereditary cerebral hemorrhage with amyloido\i\. Dutch type, revealed that the cysteine proteinase inhibitor cystatin C. colocalirr\ wth amyloid P-protein (AP) in parenchymal and vascular amyloid deposlta. ltnmunoelectronmicroacopy demonstrated dual staming of amyloid fibrila with anti-Apand anti-cyst&in C antibodia. Cyatatln C immunoreactivity wa\ alw obswved in smyloid deposits m the brain of transgenic mice overexpressing human &unylold precursor protein. Although massive depositmn of variant cystatin C in the cerebral vessels of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosia is thought to be responsible for the pathological proces\ea leading to stroke, our data do not support the view that colocalization of wild-type cystatin C with APincreases the risk of cerebral hemorrhage in Alrheimer’s discase patients. Furthermore, a subpopulation of neurons withm the cortical region most liable to amyloid deposition m the brains of Alrheimer‘s disease patlenta was strongly stained with anti-cyatatin C antibodies. lmmunohistochemlcal analysis with antibodies specific fcx the carhoxyl-terminus of API-42 ahowed intracellular immunoreactivity m the sane neuronal population immunoreactive with the anti-cystatin antibody. It remains to be determined whether the asaouation of cyrtatin C and A(jis a primary factor in amyloidogeneGr in Alrheimsr’\ diwase or is a late event in which the protein is absorbed onto the prewou\ly fornxd A@amyloid fihril\.
p%iJ Pioli
THE ROLE OF MITOGEN ACTIVATED PROTEIN KINASES IN COMPLEMENT ANAPHYLATOXIN CSA MEDIATED NEUROPROTECTION
Mukhrrjee.
Gurlw
M Painrttr,
Mount
Sinai
Sch of Medicitw.
New
York. NY
The complement system, a major component of inflammatory responses, has often been implicated in neurodegmerative conditions such as Al/.hamer’s disease (AD). Contrary to cla%ical hypotheses of the complement as mediator of pathogenesi\. we previously found that mice genetically deficient in the complement component CS were more uxcptible to excitotoxic neurodegeneration. More recently. we tound that CS-derived anaphylatoxin CSa may block neuronal apoptotic death through the Inhibition of caspase actiwlion. Bawd on evidence that C5a inhihlts npoptotic death
Presentution:
Psychosociul
Studies
I
in circulating inflammatory cells through the regulation of mitogen activated protein kmax (MAPK) pathwayr, we explored similar mechanisms in brain cells. Using murine primary conico-hippocampal neuron cultures, we found a tune dependent induction of extracellular signal-regulated kinase (ERK)-I and ERK2 in response to treatment with human recombinant (hr)CSa. This induction was prevented by pretreatment with the C5a receptor antagonist Clll. Therefore. we further explored the role of MAPKF in C5a mediated neuroprotection. We found that the MAPK inhibitor PD98059 prevented hrCSa mediated protection against glutamate toxicity coincidental to inhibition of caspase 3 activation in neuron. This novel neuroprotective role of C5a complicate5 current theories of complement proteins as proinflammatory mediators of neurodegeneration in AD. Since the complement system represents a target for therapeutic intervention in AD, further characterization of the complex role of complement proteins in the brain ir essential. We are presently using C5aR-KO mice to study the role of C5a m mechanism\ of apoptotic death in response to glutamate or fi-amyloid brain Icsion\.
Poster Presentation:
Isss]
Psychosocial
Studies I
LONGITUDINAL STUDY OF PSYCHOLOGICAL CAREGIVERS OF MILD DEMENTED PATIENTS.
BURDEN
IN
Objective: The present study examinea changes over time of psychological burden in caregivers of mild demented patients. Methods: This study evaluated a sample of 101 wbjectq recruited at the Alhheimer’s Unit of Brescia, Italy. Demented patient\ underwent a multidimensional aaaesament, Caregivers answered the questionnaire Including: sociodemographic variables, objective burden indicators and outcome variables examined wth the Caregiver Burden Inventory (CBI) which measures five factors: Time-Dependence, Developmental burden, Physical burden, Social burden and Emotional burden. The baseline asbebsment (TO) was followed by two evaluation\ al 12 (Tl?) and 24 months (T24). Rewltx Caregivers were 67.3% female; the mean age was 54.X? 13.3. They were most Frequently adult children (44.6%); 55.4% were living with the patient. Patients (65.3% female. mean age 731-X.4) had a mean Mini Mental State Examination (MMSE) wore of 22.21-3.8, where the Neuropsychiatric Inventory (NPI) total xore was 21. I t 14.0 and Barthel Index score WIF 90.7?9.3. In a repeated measure analysis of variance, we found differential changes in time for caregiver \ psychological variables. Developmental hurden mcrease in the first yea of the study (p=O.O20) and then stabilized at the two year follow up (p=n.~.). ‘Time-Dependence burden and Physical burden increased linearly in the two years of observation (TO=6.4?5.3; Tl2=8.4?5.X: T24= I0.1tS.7; p=O.OOO and 7‘0=2.4?3.1: 712=3.4?3.9: T24=3.8+3.9: p=O.O05. respectively). EmotIonal burden increased in the last year OF observatmn (Tl2=2.4?3.l: T24=3.6+-4.9: p=O.O27). ConcluGon: Thcw findings indicate that Feeling\ of burden folio\\ different trajectories. The Developmental burden mcrea\ed in the first year of caregiving and then wems to adapt to the responsibilities of the new role. Objective burden (Time-Dependence and Physical burden) ic linearly associated to the increaaing demands of patient s care. Feelings of shame on patient social behaviour (Emotional burden) increased in the second year in association with patient cognitive and hehavioural decline. No significant differences were ohserved for Social burden.
PROGRAM FOR CAREGIVERS OF DEMENTED PAp%GJSUPPORT TIENTS TO ADOPT TO NEW LIFE SITUATION AFTER INSTITUTIONALIZATION
OF THE PATIENT
Support program for caregivers of demented patients to adopt to new life situation after institutionalization of the patient Backround and aim of the project: Intervention programs to support caregivers of demented patients during home care have been carried out with good rewlt%. Experience of support programs for caregivers after mstitutionalization of a demented relative is scanty. Some studies have shown that placement to institution reduces caregivers stress and physical burden but it does not necessarily make caregivers life easier of reduce emotional strain. Often guilt. loneliness and depressive feelings arise. We wanted to establish an intervention program which would enable caregivers to go through different feelings, process their grief and find the ways to adopt to the new life situation. The aim in our three year project is to create a national model to be used in social and health care system when a demented patient i:, institutionalized. Pamcipants: In one area of the city of Eapoo, wuthern Finland all those informal caregiver\ providing primary support to demented patient\ will he taken to the project at the time of lnstitutionaliration. Durmp the first
Poster
iNCREASED PRESENCE OF AMINO-TERMINALLY-TRUNCATED AB-PEPTIDES IN PRESENILIN 1 EARLY-ONSET FAMILIAL ALZHEIMER DISEASE.
Extracellular amyloid plaques, predominantly compowd of a 40/42 amino acid peptide defined as amyloid P-peptide (AP), are generated through the proteolysis of the amyloid precursor protein (APP). APP, with prescnilin I (PSI) and prr\enilin 2 (PS2) are the three known proteins linked to the etiology of Inherited. autosomal dominant forlns of AD. The physiological functions and the pathological effect\ of presenilin\ in AD are, at the moment, specula~we. In search for a direct evidence of PSI influence in the formation of AD peptides we analyzed the soluble AD in brain extracts from subjecta with mutated PSI and APP gcnea. in companwn to sporadic AD cases. Immunoprecipiration ot hram extracted Ab peptldes followed by gel electrophoresis and Western Blotting revealed that the production of NH2-terminally truncated AP peptide\ mainly starting at position 11, either with or without a pyroglutamate modification in this residue, is significantly (p
lssjl
CODEPOSITION OF CYSTATIN C WITH AMYLOID-BPROTEIN IN THE BRAIN OF ALZHEIMER’S DISEASE PATIENTS
Immunohistochemical analysis of brains of patients with Alrheimer’? disease and of patients with hereditary cerebral hemorrhage with amyloido\i\. Dutch type, revealed that the cysteine proteinase inhibitor cystatin C. colocalirr\ wth amyloid P-protein (AP) in parenchymal and vascular amyloid deposlta. ltnmunoelectronmicroacopy demonstrated dual staming of amyloid fibrila with anti-Apand anti-cyst&in C antibodia. Cyatatln C immunoreactivity wa\ alw obswved in smyloid deposits m the brain of transgenic mice overexpressing human &unylold precursor protein. Although massive depositmn of variant cystatin C in the cerebral vessels of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosia is thought to be responsible for the pathological proces\ea leading to stroke, our data do not support the view that colocalization of wild-type cystatin C with APincreases the risk of cerebral hemorrhage in Alrheimer’s discase patients. Furthermore, a subpopulation of neurons withm the cortical region most liable to amyloid deposition m the brains of Alrheimer‘s disease patlenta was strongly stained with anti-cyatatin C antibodies. lmmunohistochemlcal analysis with antibodies specific fcx the carhoxyl-terminus of API-42 ahowed intracellular immunoreactivity m the sane neuronal population immunoreactive with the anti-cystatin antibody. It remains to be determined whether the asaouation of cyrtatin C and A(jis a primary factor in amyloidogeneGr in Alrheimsr’\ diwase or is a late event in which the protein is absorbed onto the prewou\ly fornxd A@amyloid fihril\.
p%iJ Pioli
THE ROLE OF MITOGEN ACTIVATED PROTEIN KINASES IN COMPLEMENT ANAPHYLATOXIN CSA MEDIATED NEUROPROTECTION
Mukhrrjee.
Gurlw
M Painrttr,
Mount
Sinai
Sch of Medicitw.
New
York. NY
The complement system, a major component of inflammatory responses, has often been implicated in neurodegmerative conditions such as Al/.hamer’s disease (AD). Contrary to cla%ical hypotheses of the complement as mediator of pathogenesi\. we previously found that mice genetically deficient in the complement component CS were more uxcptible to excitotoxic neurodegeneration. More recently. we tound that CS-derived anaphylatoxin CSa may block neuronal apoptotic death through the Inhibition of caspase actiwlion. Bawd on evidence that C5a inhihlts npoptotic death
Presentution:
Psychosociul
Studies
I
in circulating inflammatory cells through the regulation of mitogen activated protein kmax (MAPK) pathwayr, we explored similar mechanisms in brain cells. Using murine primary conico-hippocampal neuron cultures, we found a tune dependent induction of extracellular signal-regulated kinase (ERK)-I and ERK2 in response to treatment with human recombinant (hr)CSa. This induction was prevented by pretreatment with the C5a receptor antagonist Clll. Therefore. we further explored the role of MAPKF in C5a mediated neuroprotection. We found that the MAPK inhibitor PD98059 prevented hrCSa mediated protection against glutamate toxicity coincidental to inhibition of caspase 3 activation in neuron. This novel neuroprotective role of C5a complicate5 current theories of complement proteins as proinflammatory mediators of neurodegeneration in AD. Since the complement system represents a target for therapeutic intervention in AD, further characterization of the complex role of complement proteins in the brain ir essential. We are presently using C5aR-KO mice to study the role of C5a m mechanism\ of apoptotic death in response to glutamate or fi-amyloid brain Icsion\.
Poster Presentation:
Isss]
Psychosocial
Studies I
LONGITUDINAL STUDY OF PSYCHOLOGICAL CAREGIVERS OF MILD DEMENTED PATIENTS.
BURDEN
IN
Objective: The present study examinea changes over time of psychological burden in caregivers of mild demented patients. Methods: This study evaluated a sample of 101 wbjectq recruited at the Alhheimer’s Unit of Brescia, Italy. Demented patient\ underwent a multidimensional aaaesament, Caregivers answered the questionnaire Including: sociodemographic variables, objective burden indicators and outcome variables examined wth the Caregiver Burden Inventory (CBI) which measures five factors: Time-Dependence, Developmental burden, Physical burden, Social burden and Emotional burden. The baseline asbebsment (TO) was followed by two evaluation\ al 12 (Tl?) and 24 months (T24). Rewltx Caregivers were 67.3% female; the mean age was 54.X? 13.3. They were most Frequently adult children (44.6%); 55.4% were living with the patient. Patients (65.3% female. mean age 731-X.4) had a mean Mini Mental State Examination (MMSE) wore of 22.21-3.8, where the Neuropsychiatric Inventory (NPI) total xore was 21. I t 14.0 and Barthel Index score WIF 90.7?9.3. In a repeated measure analysis of variance, we found differential changes in time for caregiver \ psychological variables. Developmental hurden mcrease in the first yea of the study (p=O.O20) and then stabilized at the two year follow up (p=n.~.). ‘Time-Dependence burden and Physical burden increased linearly in the two years of observation (TO=6.4?5.3; Tl2=8.4?5.X: T24= I0.1tS.7; p=O.OOO and 7‘0=2.4?3.1: 712=3.4?3.9: T24=3.8+3.9: p=O.O05. respectively). EmotIonal burden increased in the last year OF observatmn (Tl2=2.4?3.l: T24=3.6+-4.9: p=O.O27). ConcluGon: Thcw findings indicate that Feeling\ of burden folio\\ different trajectories. The Developmental burden mcrea\ed in the first year of caregiving and then wems to adapt to the responsibilities of the new role. Objective burden (Time-Dependence and Physical burden) ic linearly associated to the increaaing demands of patient s care. Feelings of shame on patient social behaviour (Emotional burden) increased in the second year in association with patient cognitive and hehavioural decline. No significant differences were ohserved for Social burden.
PROGRAM FOR CAREGIVERS OF DEMENTED PAp%GJSUPPORT TIENTS TO ADOPT TO NEW LIFE SITUATION AFTER INSTITUTIONALIZATION
OF THE PATIENT
Support program for caregivers of demented patients to adopt to new life situation after institutionalization of the patient Backround and aim of the project: Intervention programs to support caregivers of demented patients during home care have been carried out with good rewlt%. Experience of support programs for caregivers after mstitutionalization of a demented relative is scanty. Some studies have shown that placement to institution reduces caregivers stress and physical burden but it does not necessarily make caregivers life easier of reduce emotional strain. Often guilt. loneliness and depressive feelings arise. We wanted to establish an intervention program which would enable caregivers to go through different feelings, process their grief and find the ways to adopt to the new life situation. The aim in our three year project is to create a national model to be used in social and health care system when a demented patient i:, institutionalized. Pamcipants: In one area of the city of Eapoo, wuthern Finland all those informal caregiver\ providing primary support to demented patient\ will he taken to the project at the time of lnstitutionaliration. Durmp the first