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Pathology of flemish APP692 Alzheimer's disease suggests that core containing plaques are angiocenteric
S66
LEWY BODY PATHOLOGY HEIMER’S DISEASE.
IN FAMILIAL (PRESENILIN-2)
ALZ-
Objective: Lrwy body (LB) pathology has been reported to occur in 20 to 30% of sporadic AD casec. However, recent evidence in AD associated with prescnilin-1 mutation\ and Down syndrome found LB pathology in at least 50% of cases. We examined the frequency of LB an additional genetic subgroup of AD, Volga German\ with the Nl411 presenilin-2 (PS-2) mutation. Methodr: Eleven cases with a PS-2 mutation were stained with H&E in the suhstantia nigra. Additional staining included H&E after deplgmentation of the subrtantia nigra and alpha-synuclein and ubiquitm/ tau immunostaining of brainstem, cmtex, amygdala and hippocampal sections. Results: Six of eleven case\ (55%) with a PS-2 mutation demonstrated LB pathology. All LB positive cases demonstrated LB pathology in both rubrtantia nigra and extra-nigral \ite\. Immunostaining with alpha-synuclein. sampling of extra-substantia nigra region\ and depigmentatlon of stained substantia nigra wztions improved OUI ability to detect LB. Concluwn: This is the third genetic subtype of AD with a 50% or greater frequency of LB pathology. The frequency of LB pathology appears to bc greater in genetic formr of AD than in sporadic. Future neuropathological studies of LB-zwociated dementia should use optimal staining method\. m&ding both alpha-synuclein immunostaining and extra-nigral umpling.
p!zJ
A S52R MUTATION IN NEUROSERPIN IS ASSOCIATED MYOCLONIC EPILEPSY AND DEMENTIA
WITH
Neuroserpin is a wine proteae tnhibitor which is highly expressed in the central nrr\ous system. Recently, it has been shown that intraneuronal neuroserpin incluw)n\ are associated with a form of prraenile dementia. We report that deposition of mutant ncuroserpin is awxiated with myoclonic epilepsy and dementia m a family. The \yndromr i\ inherited as an autowmal dominant trait with onxt in the third decade of life. We now report on the characterization of the intranruronal incluw~w and their compo&on. At autopsy, brain slices were frozen at -70 degrees Celws. Tissue from the frontal cortex was then thawed and intmneuronal inclusions were isolated by homogemratmn and differential centrifugation. The inclusmnr were then solubilized 111guanidmr hydrochloride and the proteins fractionated by gel filtration chromatography. SDS-PAGE analysis rhowed one prominent band of approximately 50 kD. Amino acid xquencing identified the major icolated protein as neuroserpin with an N terminus ctatting at pailion 20 when compared to the neuroaerpin originally characterlred in the chlcken. Thi\ cuggeyts that in humans, mature neuroserpin I\ three residues shorter at the amino terminus than that of the chicken which start5 at residue 17. In addition, a wb5titution of arginine for serine at position 52 of the putative expressed protein (which includes a 19 amino acid residue signal peptide) wu identified. Nucleottde sequencing of genomic DNA isolated from the affected individual revealed heterozygosity with both Adenine and Cytoaine at the position corresponding to the first base of codon 52 of the Neurmrrpin gene. confirming the results obtained from the protem sequence. We hypothesis that this mutalon result\ m abnormal metabohsm of neuroaerpin and accumulation in intraneuronal deposit\. The neuronal dysfunction rewlting from both the mutated neuroserpin and the neuroserpln deposition i\ mwt likely the cause of the myoclonic epilrp\y and dt?mrntla.
PLAQUE-INDUCED NEURITE ABNORMALITIES IN TG2576 HAPPSW OVER-EXPRESSING TRANSGENIC MICE: SPECIAL ROLE OF THIOFLAVINE S PLAQUES AND IMPLICATIONS FOR DISRUPTION OF THE NEUROPIL
WC have earlier \hon n that. I” AD, compact amyloid deposit\ are awxiated with a marked chamcterl\tlc alteration\ ln dendritic geomrtry (Knowle\ RB. ct al. Plaque inductxl nruritr ahnormalities: imphcatmna for di\ruptlon of neural networks m Al7helmcr’\ direaw. Proc Nat1 Acad Sci USA 1999. 96:5274-5279). We now examined APPSw over-expre,\inp rnw which develop amyloid depowc, wth mcreasmg age. At bowline. there appear\ to he an alteration in dendritic morphology
with increased curvilinear distance in APP overexpressmg mice, compared to nontransgenic littermate controls. This increase in curvilinear distance is only altered slightly within diffuse amyloid deposits, but is increased dramatically within the boundaries of thioflavine S positive amyloid deposits. Thioflavine S positive plaque\. unlike diffuse plaques, are also associated with a significant diminution in the density of dendrites and neuronal cell bodies. The area immediately surrounding thiotlavine S positive plaques are minimally affected. Thew results suggest that thioflavine S positive plaques affect the neuropil in a unique fashion, leading to a marked disruption of the dendritic architecture and potentially to disruption of neural networks. These results suggert that the T&2576 mouse recapitulates this aspect of AD pathology as vVel1.
p!wJ
PATHOLOGY OF FLEMISH APP692 ALZHEIMER’S DISEASE SUGGESTS THAT CORE CONTAINING PLAQUES ARE ANGIOCENTERIC
It is generally believed that diffuse, neurocrnteric amylold deposits mature over time with formation of discrete nidi that eventually become core-containing senile plaque\ m brains of Alzheimer’s disease (AD) patients. We earlier described a Dutch family segregating an APP A692G (Flemish) mutation that presented clinically and newpathologically with a combined picture of AD and congophihc amyloid angiopathy. A closer examination of two APP692 cases revealed that plaques cores are vtenosed blood vessels clogged wth AP amyloid. On serial 2krn thick paraffin embedded sections and using blood veswl markers like CD34, CD31, n-rmooth-muscle-actin. and collagen-l, many of these cores were shown to contain a lumen. This was also confirmed on confocal laser scanning microscopy and electron microscopy. We hypothesized that if these blood vessels are clogged, it would require the production of new blood vessels. Indeed these partially clogged vessels produced abundant vaxxlar endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGl+). Furthermore, plaque cores and dyshoric amyloid deposits in APP692. PSENl AD. sporadic AD, and Down’s syndrome cases are composed of ApI-40. Converxly, AP42 N-terminally cleaved at either El or L17 (~3) constitute the diffuse noncompact plaques. lmmunoreactivity to N-terminal AP antibodies further demon\trated that fractal profile of core periphery is similar to that of dyshoric amylold depoait. Contextual morphology with glial cells showed that microglias are clorely associated with the plaque cores, surrounding and entangling them and perhap\ possibly contributing to their growth. Our data indicate that the core containing plaque\ could be generally derived from stenosed vessels clogged by AD that serve a\ a nidua for further deposition and progression of senile plaques. We also propose at least two distinct sources of Afi secretion wth a slightly different APP processing. One imparts vascular deposits which facilitates the formation of compact plaque\. The other favors formation of diffuse plaque\ and secondary deposits around cores. THE IMPACT OF CEREBROVASCULAR MER PATHOLOGY IN THE ELDERLY
DISEASE ON ALZHEI-
Cerebrovascular disease (CVD) and Alrheimer’\ diwxe (AD) are common causes of dementia !n the elderly. Prospective clinical \tudir\ suggest the risk of AD I\ \Ipnificantly mcreased after event>, which cause CVD. Episodes of stroke or cerebrovascular inodents are known to worsen cognitive decline in patients with preexisting AD. Review of varmus con\ortum data shows that more than a third of AD cases exhibit variable cerebrovaccular pathology beside\ amyloid p (AP) plaque\ and tangles. Whether these vascular lesions are coincidental or caual in the pathogenetic procaaes leading to AD remains to be defined. We examined a necropsy aerier to establish whether CVD or cerebral infarctmn is related to acquisition of markers of Al~heimer pathology in AD. Our findings showed that there was a significant (ANOVA) age-dependent accumulation of total amyloid p 42 species in the temporal cortex of vascular dementia (VaD) patients and reached to concentrations (15-20 nmoll g wt) comparable to those in AD subjects in the 8th decade. While there was alro an age-dependent increase in AP 42 in the controls. the concentrations were considerably lower compared to VaD and AD patients. In keeping with previou reports AD 40 concentrations were consistently low by several fold and there was no evidence for a consistent age-dependent increase. Previous studies have shown mcreases in CSF hyperphwphorylated tau are not restricted to AD but alro evident m various form\ of VaD. We wggest that markers of Allheimer pathology are
LEWY BODY PATHOLOGY HEIMER’S DISEASE.
IN FAMILIAL (PRESENILIN-2)
ALZ-
Objective: Lrwy body (LB) pathology has been reported to occur in 20 to 30% of sporadic AD casec. However, recent evidence in AD associated with prescnilin-1 mutation\ and Down syndrome found LB pathology in at least 50% of cases. We examined the frequency of LB an additional genetic subgroup of AD, Volga German\ with the Nl411 presenilin-2 (PS-2) mutation. Methodr: Eleven cases with a PS-2 mutation were stained with H&E in the suhstantia nigra. Additional staining included H&E after deplgmentation of the subrtantia nigra and alpha-synuclein and ubiquitm/ tau immunostaining of brainstem, cmtex, amygdala and hippocampal sections. Results: Six of eleven case\ (55%) with a PS-2 mutation demonstrated LB pathology. All LB positive cases demonstrated LB pathology in both rubrtantia nigra and extra-nigral \ite\. Immunostaining with alpha-synuclein. sampling of extra-substantia nigra region\ and depigmentatlon of stained substantia nigra wztions improved OUI ability to detect LB. Concluwn: This is the third genetic subtype of AD with a 50% or greater frequency of LB pathology. The frequency of LB pathology appears to bc greater in genetic formr of AD than in sporadic. Future neuropathological studies of LB-zwociated dementia should use optimal staining method\. m&ding both alpha-synuclein immunostaining and extra-nigral umpling.
p!zJ
A S52R MUTATION IN NEUROSERPIN IS ASSOCIATED MYOCLONIC EPILEPSY AND DEMENTIA
WITH
Neuroserpin is a wine proteae tnhibitor which is highly expressed in the central nrr\ous system. Recently, it has been shown that intraneuronal neuroserpin incluw)n\ are associated with a form of prraenile dementia. We report that deposition of mutant ncuroserpin is awxiated with myoclonic epilepsy and dementia m a family. The \yndromr i\ inherited as an autowmal dominant trait with onxt in the third decade of life. We now report on the characterization of the intranruronal incluw~w and their compo&on. At autopsy, brain slices were frozen at -70 degrees Celws. Tissue from the frontal cortex was then thawed and intmneuronal inclusions were isolated by homogemratmn and differential centrifugation. The inclusmnr were then solubilized 111guanidmr hydrochloride and the proteins fractionated by gel filtration chromatography. SDS-PAGE analysis rhowed one prominent band of approximately 50 kD. Amino acid xquencing identified the major icolated protein as neuroserpin with an N terminus ctatting at pailion 20 when compared to the neuroaerpin originally characterlred in the chlcken. Thi\ cuggeyts that in humans, mature neuroserpin I\ three residues shorter at the amino terminus than that of the chicken which start5 at residue 17. In addition, a wb5titution of arginine for serine at position 52 of the putative expressed protein (which includes a 19 amino acid residue signal peptide) wu identified. Nucleottde sequencing of genomic DNA isolated from the affected individual revealed heterozygosity with both Adenine and Cytoaine at the position corresponding to the first base of codon 52 of the Neurmrrpin gene. confirming the results obtained from the protem sequence. We hypothesis that this mutalon result\ m abnormal metabohsm of neuroaerpin and accumulation in intraneuronal deposit\. The neuronal dysfunction rewlting from both the mutated neuroserpin and the neuroserpln deposition i\ mwt likely the cause of the myoclonic epilrp\y and dt?mrntla.
PLAQUE-INDUCED NEURITE ABNORMALITIES IN TG2576 HAPPSW OVER-EXPRESSING TRANSGENIC MICE: SPECIAL ROLE OF THIOFLAVINE S PLAQUES AND IMPLICATIONS FOR DISRUPTION OF THE NEUROPIL
WC have earlier \hon n that. I” AD, compact amyloid deposit\ are awxiated with a marked chamcterl\tlc alteration\ ln dendritic geomrtry (Knowle\ RB. ct al. Plaque inductxl nruritr ahnormalities: imphcatmna for di\ruptlon of neural networks m Al7helmcr’\ direaw. Proc Nat1 Acad Sci USA 1999. 96:5274-5279). We now examined APPSw over-expre,\inp rnw which develop amyloid depowc, wth mcreasmg age. At bowline. there appear\ to he an alteration in dendritic morphology
with increased curvilinear distance in APP overexpressmg mice, compared to nontransgenic littermate controls. This increase in curvilinear distance is only altered slightly within diffuse amyloid deposits, but is increased dramatically within the boundaries of thioflavine S positive amyloid deposits. Thioflavine S positive plaque\. unlike diffuse plaques, are also associated with a significant diminution in the density of dendrites and neuronal cell bodies. The area immediately surrounding thiotlavine S positive plaques are minimally affected. Thew results suggest that thioflavine S positive plaques affect the neuropil in a unique fashion, leading to a marked disruption of the dendritic architecture and potentially to disruption of neural networks. These results suggert that the T&2576 mouse recapitulates this aspect of AD pathology as vVel1.
p!wJ
PATHOLOGY OF FLEMISH APP692 ALZHEIMER’S DISEASE SUGGESTS THAT CORE CONTAINING PLAQUES ARE ANGIOCENTERIC
It is generally believed that diffuse, neurocrnteric amylold deposits mature over time with formation of discrete nidi that eventually become core-containing senile plaque\ m brains of Alzheimer’s disease (AD) patients. We earlier described a Dutch family segregating an APP A692G (Flemish) mutation that presented clinically and newpathologically with a combined picture of AD and congophihc amyloid angiopathy. A closer examination of two APP692 cases revealed that plaques cores are vtenosed blood vessels clogged wth AP amyloid. On serial 2krn thick paraffin embedded sections and using blood veswl markers like CD34, CD31, n-rmooth-muscle-actin. and collagen-l, many of these cores were shown to contain a lumen. This was also confirmed on confocal laser scanning microscopy and electron microscopy. We hypothesized that if these blood vessels are clogged, it would require the production of new blood vessels. Indeed these partially clogged vessels produced abundant vaxxlar endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGl+). Furthermore, plaque cores and dyshoric amyloid deposits in APP692. PSENl AD. sporadic AD, and Down’s syndrome cases are composed of ApI-40. Converxly, AP42 N-terminally cleaved at either El or L17 (~3) constitute the diffuse noncompact plaques. lmmunoreactivity to N-terminal AP antibodies further demon\trated that fractal profile of core periphery is similar to that of dyshoric amylold depoait. Contextual morphology with glial cells showed that microglias are clorely associated with the plaque cores, surrounding and entangling them and perhap\ possibly contributing to their growth. Our data indicate that the core containing plaque\ could be generally derived from stenosed vessels clogged by AD that serve a\ a nidua for further deposition and progression of senile plaques. We also propose at least two distinct sources of Afi secretion wth a slightly different APP processing. One imparts vascular deposits which facilitates the formation of compact plaque\. The other favors formation of diffuse plaque\ and secondary deposits around cores. THE IMPACT OF CEREBROVASCULAR MER PATHOLOGY IN THE ELDERLY
DISEASE ON ALZHEI-
Cerebrovascular disease (CVD) and Alrheimer’\ diwxe (AD) are common causes of dementia !n the elderly. Prospective clinical \tudir\ suggest the risk of AD I\ \Ipnificantly mcreased after event>, which cause CVD. Episodes of stroke or cerebrovascular inodents are known to worsen cognitive decline in patients with preexisting AD. Review of varmus con\ortum data shows that more than a third of AD cases exhibit variable cerebrovaccular pathology beside\ amyloid p (AP) plaque\ and tangles. Whether these vascular lesions are coincidental or caual in the pathogenetic procaaes leading to AD remains to be defined. We examined a necropsy aerier to establish whether CVD or cerebral infarctmn is related to acquisition of markers of Al~heimer pathology in AD. Our findings showed that there was a significant (ANOVA) age-dependent accumulation of total amyloid p 42 species in the temporal cortex of vascular dementia (VaD) patients and reached to concentrations (15-20 nmoll g wt) comparable to those in AD subjects in the 8th decade. While there was alro an age-dependent increase in AP 42 in the controls. the concentrations were considerably lower compared to VaD and AD patients. In keeping with previou reports AD 40 concentrations were consistently low by several fold and there was no evidence for a consistent age-dependent increase. Previous studies have shown mcreases in CSF hyperphwphorylated tau are not restricted to AD but alro evident m various form\ of VaD. We wggest that markers of Allheimer pathology are