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Mechanism of gelsolin-mediated inhibition of fibrillization of amyloid beta-protein
Poster Presentation:
Alzheimer’.~
Disease and Related
Dementias
IV
MECHANISM OF GELSOLIN-MEDIATED INHIBITION FIBRILLIZATION OF AMYLOID BETA-PROTEIN
S217
OF
Amyloid beta-protein (AP) is present normally in cerebrospinal fluid (CSF) and plasma. However, in the brains of patients with Alzheimer‘s disease (AD), AP is deposited in the fibrillar form. Recently, we have reported that gelsolin. a secreted protein in the plasma and CSF, binds to AD, and inhibits ita tibrilliration. The aim of this study was to investigate the mechanism of gelsolin-mediated inhibition of AP fibrillogenesis. We studied the effect of gelsolin on aggregation, nucleation event and growth phase of AP fibril formation. Our results indicate that gelaolin decreases the nucleation time and increaser the initial aggregation of AD, but inhibits the growth phase and thus, the fibril formation and its elongation. When the freshly solubilired AP was added to the nuclei of AB alone and AP + gelsolin, the nuclei of A@ alone could grow further while the growth was not observed with nuclei of AD + gelsolin. It i?. suggested that gelsolin inhibits fibril formation by capping the aggregated A@ in a manner analogous to the capping of actin polymer< by gelsolin. We reported previously that worn promotes the oligomeri7ation and initial aggregation of A@. but inhibits its fibrillization. Since cerum contams gelsolin. we now yugge?t that gelrolin may be the factor which contributed to there changes by serum.
EFFECTS OF APOI’TOSIS ON THE SECRETION AND PROCESSING OF BETA-SECRETASE CLEAVED AMYLOID PRECURSOR PROTEIN IN PRIMARY RAT CORTICAL CULTURES Kristinu Sennvik, NEUROTEC. Karolinska Institute. Huddinge Sweden: Johan Fastborn. Kumlimku Inst. Huddingr Swrdm: Bengt Winhlad, Eirikur Benediki. NEUROTEC, Kumlinsku Institute, Huddingr Sweden; Maria Ankurcrona. Karolinsk~r lmt, Huddinge Sweden Alrheimer‘s disease (AD) is characterised by the degeneration and loss of neurons, extracellular aenile plauqea consisting mainly of P-amyloid (AP), and intracellular neurofibrillary tangles. Programmed cell death, apoptoais, has been recognired as a potentially important mechanism involved in the initiation and progression of neuronal los\ in AD. Neuronal apoptosis was induced in primary rat cortical culture\ through treatment with the calcium ionophore A23187. which simulates glutamate toxicity by enhancing the calcium influx into the cell. The levels of wxeted soluble APP were measured and the levels of p-aecretase cleaved APP were found to be significantly lower in the rat cortical cultures exposed to the calcium ionophore. indicating specific apoptosis related changes in APP processing. The induction of apoptosis, as opposed to necrosis, was confirmed by MTT assays as well as annexin and propidium iodide staining
CLINICAL AND BRAIN BIOPSY FINDINGS IN POSSIBLE 19871PATHIC NORMAL-PRESSURE HYDROCEPHALUS Rachid A Beth, Flrmming Gjerris, Anne-Margrethe Rigshospitalet, Copenhagen Denmark
IDIO-
Nissen, Mrrrinnrw Juhler.
In patients suspected of idiopathic norm&pressure hydrocephalua (INPH) it is speculated, whether cerebral parenchymal changes induced by degenerative or arteriosclerotic disorders are involved in the pathophyriology. In the prerent prospectwe study 3X consecutive patxnts, referred with a clinicoradiological suspicion of INPH, underwent a thorough clinical evaluation and frontal cerebral biopsy ampling. Special emphasis was put on the clinical and/or neuropathological prerence of cerebrovascular disease (CVD) and Alzheimer’y disease (AD). Only 29 patients fulfilled rigorous clinical, radiological and hydrodynamic shunt criteria and underwent shunt operation, independently of the cerebral biopsy findings or chnically diagnosed concomitant disorders. Only 33 percent of the shunted patients improved. Pathological parenchymal changes were described in over half of the biopsies, with Alrheimer changes (n = 9) and vascular changes (n = 9) being the most frequent findings. Seventy-four percent of all patients and 89 percent of the shunted patienta presented one or several concurrent disorders, most frequently CVD, which was diagnosed in over half of the evaluated patients and two thirds of the shunted patients. Half of the evaluated patients fulfilled the NINCS-ADRDA criteria for possible AD; the remaining fulfilled criteria for unlikely AD. No correlation was found between the cerebral parenchymal findings of AD or CVD and the clinical diagnoses of AD and CVD respectively. The presence of pathological cerebral parenchymal changes did not preclude a clinical improvement after shunt operation, but the clinicoradiological diagnosis of CVD was associated with a poor outcome. The heterogeneous clinical and cerebral biopsy findings support the perception of INPH as a multietiological clinical entity. Consequently, in the preoperative evaluation of patients with possible INPH, it is essential to assess the presence of various concomitant non shunt treatable conditions, including degenerative and vascular related brain disorders, and their
relative contribution to the symptomatology. The evaluation thus seem& a multidisciplinary task involving both neurological and neurowrgical \peciahties.
CLINICAL AND NEUROANATOMICAL MIRROR SIGN IN FRONTOTEMPORAL HEIMER’S DISEASE
CORRELATES OF THE DEMENTIA AND ALZ-
Mirror sign or the misrecognition of the own self as another person when in front of a mirror has been described as a rare phenomena in some forms of dementia, but ita neuroanatomical subwate remaina unclear. Moreover, the study of its climcal correlates dewrves more attention. A\ a objective, we focus on mirror sign in FTD and in AD searchmg for data that could offer Insight into the possible pathophisiological mechanisms related with this Ggn. The response of 20 FTD and 22 AD patients placed in front of a mirror of natural size was observed. SPECT fans were performed in all the patients in the same period. F&her Exact Teat was u\ed to verify the association between the presence (or not) of mmor sign wth the presence (or not) of the frontal hypoperfusion. confabulation and low wares in the MMSE (an mdirect measure of the severety of the dementia process). Prosopagnosia for their own faces was investigated in both dementia groups in order to verify if it can explain the mirror sign. Among FTD patients, eight (40%) presented the sign. Among AD patients, seven (31,8%) presented. AD group failed to show a $igmficant aswciation between frontal involvement and mirror sign (p=O.O65), but when the subgroup of AD patients with frontal involvement was considered in part, it showed a significant association and showed a tendency to behavior as the FTD group. A strong association between confabulations and low scores in the MMSE with mirror sign was observed in both AD and mD groups (p
piej
FAMILY CAREGIVERS’
WILLINGNESS
TO PAY (WTP)
The atm of the present study was to examine the wdlingnesa of family members caring for elderly persons ruffering from AD to pay for drug treatment wing the contingent analysis technique and the theory of reasoned action. Two-hundred and twenty family members (68.2% F, mean age=62.3; 59.8% spouse< and the rest children) were interviewed regarding their WTP for drug treatment,thier attitudes and beliefs regarding paying for the medication and their knowledge about AD. The maximum price caregivers were willing to pay ranged between 50%150% the actual cost of the medication. The price participants were willing to pay reflected not only economic fatora (i.e., income) but also attitudes and perceptions regarding affordabililty and normative expectations of important others. Knowledge about drug treatment was one of the main correlate\ of WTP. Education programs to optimize deciaionmaking procerrea, wth special attentmn to caregivers‘ attitude\ are diccwsed.
Alzheimer’.~
Disease and Related
Dementias
IV
MECHANISM OF GELSOLIN-MEDIATED INHIBITION FIBRILLIZATION OF AMYLOID BETA-PROTEIN
S217
OF
Amyloid beta-protein (AP) is present normally in cerebrospinal fluid (CSF) and plasma. However, in the brains of patients with Alzheimer‘s disease (AD), AP is deposited in the fibrillar form. Recently, we have reported that gelsolin. a secreted protein in the plasma and CSF, binds to AD, and inhibits ita tibrilliration. The aim of this study was to investigate the mechanism of gelsolin-mediated inhibition of AP fibrillogenesis. We studied the effect of gelsolin on aggregation, nucleation event and growth phase of AP fibril formation. Our results indicate that gelaolin decreases the nucleation time and increaser the initial aggregation of AD, but inhibits the growth phase and thus, the fibril formation and its elongation. When the freshly solubilired AP was added to the nuclei of AB alone and AP + gelsolin, the nuclei of A@ alone could grow further while the growth was not observed with nuclei of AD + gelsolin. It i?. suggested that gelsolin inhibits fibril formation by capping the aggregated A@ in a manner analogous to the capping of actin polymer< by gelsolin. We reported previously that worn promotes the oligomeri7ation and initial aggregation of A@. but inhibits its fibrillization. Since cerum contams gelsolin. we now yugge?t that gelrolin may be the factor which contributed to there changes by serum.
EFFECTS OF APOI’TOSIS ON THE SECRETION AND PROCESSING OF BETA-SECRETASE CLEAVED AMYLOID PRECURSOR PROTEIN IN PRIMARY RAT CORTICAL CULTURES Kristinu Sennvik, NEUROTEC. Karolinska Institute. Huddinge Sweden: Johan Fastborn. Kumlimku Inst. Huddingr Swrdm: Bengt Winhlad, Eirikur Benediki. NEUROTEC, Kumlinsku Institute, Huddingr Sweden; Maria Ankurcrona. Karolinsk~r lmt, Huddinge Sweden Alrheimer‘s disease (AD) is characterised by the degeneration and loss of neurons, extracellular aenile plauqea consisting mainly of P-amyloid (AP), and intracellular neurofibrillary tangles. Programmed cell death, apoptoais, has been recognired as a potentially important mechanism involved in the initiation and progression of neuronal los\ in AD. Neuronal apoptosis was induced in primary rat cortical culture\ through treatment with the calcium ionophore A23187. which simulates glutamate toxicity by enhancing the calcium influx into the cell. The levels of wxeted soluble APP were measured and the levels of p-aecretase cleaved APP were found to be significantly lower in the rat cortical cultures exposed to the calcium ionophore. indicating specific apoptosis related changes in APP processing. The induction of apoptosis, as opposed to necrosis, was confirmed by MTT assays as well as annexin and propidium iodide staining
CLINICAL AND BRAIN BIOPSY FINDINGS IN POSSIBLE 19871PATHIC NORMAL-PRESSURE HYDROCEPHALUS Rachid A Beth, Flrmming Gjerris, Anne-Margrethe Rigshospitalet, Copenhagen Denmark
IDIO-
Nissen, Mrrrinnrw Juhler.
In patients suspected of idiopathic norm&pressure hydrocephalua (INPH) it is speculated, whether cerebral parenchymal changes induced by degenerative or arteriosclerotic disorders are involved in the pathophyriology. In the prerent prospectwe study 3X consecutive patxnts, referred with a clinicoradiological suspicion of INPH, underwent a thorough clinical evaluation and frontal cerebral biopsy ampling. Special emphasis was put on the clinical and/or neuropathological prerence of cerebrovascular disease (CVD) and Alzheimer’y disease (AD). Only 29 patients fulfilled rigorous clinical, radiological and hydrodynamic shunt criteria and underwent shunt operation, independently of the cerebral biopsy findings or chnically diagnosed concomitant disorders. Only 33 percent of the shunted patients improved. Pathological parenchymal changes were described in over half of the biopsies, with Alrheimer changes (n = 9) and vascular changes (n = 9) being the most frequent findings. Seventy-four percent of all patients and 89 percent of the shunted patienta presented one or several concurrent disorders, most frequently CVD, which was diagnosed in over half of the evaluated patients and two thirds of the shunted patients. Half of the evaluated patients fulfilled the NINCS-ADRDA criteria for possible AD; the remaining fulfilled criteria for unlikely AD. No correlation was found between the cerebral parenchymal findings of AD or CVD and the clinical diagnoses of AD and CVD respectively. The presence of pathological cerebral parenchymal changes did not preclude a clinical improvement after shunt operation, but the clinicoradiological diagnosis of CVD was associated with a poor outcome. The heterogeneous clinical and cerebral biopsy findings support the perception of INPH as a multietiological clinical entity. Consequently, in the preoperative evaluation of patients with possible INPH, it is essential to assess the presence of various concomitant non shunt treatable conditions, including degenerative and vascular related brain disorders, and their
relative contribution to the symptomatology. The evaluation thus seem& a multidisciplinary task involving both neurological and neurowrgical \peciahties.
CLINICAL AND NEUROANATOMICAL MIRROR SIGN IN FRONTOTEMPORAL HEIMER’S DISEASE
CORRELATES OF THE DEMENTIA AND ALZ-
Mirror sign or the misrecognition of the own self as another person when in front of a mirror has been described as a rare phenomena in some forms of dementia, but ita neuroanatomical subwate remaina unclear. Moreover, the study of its climcal correlates dewrves more attention. A\ a objective, we focus on mirror sign in FTD and in AD searchmg for data that could offer Insight into the possible pathophisiological mechanisms related with this Ggn. The response of 20 FTD and 22 AD patients placed in front of a mirror of natural size was observed. SPECT fans were performed in all the patients in the same period. F&her Exact Teat was u\ed to verify the association between the presence (or not) of mmor sign wth the presence (or not) of the frontal hypoperfusion. confabulation and low wares in the MMSE (an mdirect measure of the severety of the dementia process). Prosopagnosia for their own faces was investigated in both dementia groups in order to verify if it can explain the mirror sign. Among FTD patients, eight (40%) presented the sign. Among AD patients, seven (31,8%) presented. AD group failed to show a $igmficant aswciation between frontal involvement and mirror sign (p=O.O65), but when the subgroup of AD patients with frontal involvement was considered in part, it showed a significant association and showed a tendency to behavior as the FTD group. A strong association between confabulations and low scores in the MMSE with mirror sign was observed in both AD and mD groups (p
piej
FAMILY CAREGIVERS’
WILLINGNESS
TO PAY (WTP)
The atm of the present study was to examine the wdlingnesa of family members caring for elderly persons ruffering from AD to pay for drug treatment wing the contingent analysis technique and the theory of reasoned action. Two-hundred and twenty family members (68.2% F, mean age=62.3; 59.8% spouse< and the rest children) were interviewed regarding their WTP for drug treatment,thier attitudes and beliefs regarding paying for the medication and their knowledge about AD. The maximum price caregivers were willing to pay ranged between 50%150% the actual cost of the medication. The price participants were willing to pay reflected not only economic fatora (i.e., income) but also attitudes and perceptions regarding affordabililty and normative expectations of important others. Knowledge about drug treatment was one of the main correlate\ of WTP. Education programs to optimize deciaionmaking procerrea, wth special attentmn to caregivers‘ attitude\ are diccwsed.