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Deposition of  -Amyloid Subtypes 40 and 42 Differentiates Dementia With Lewy Bodies From Alzheimer Disease
Carol F. Lippa, MD;
Kazuharu Ozawa, PhD;
David M. A. Mann, PhD;
Kazuhiro Ishii, MD;
Thomas W. Smith, MD;
Shigeki Arawaka, MD;
Hiroshi Mori, PhD
Arch Neurol. 1999;56:1111-1118.
ABSTRACT
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Background Alterations in the metabolism of the amyloid precursor protein and the formation of  -amyloid (A) plaques are associated with neuronal death in Alzheimer disease (AD). The plaque subtype Ax-42 occurs as an early event, with Ax-40 plaques forming at a later stage. In dementia with Lewy bodies (DLB), an increase in the amount of cortical A occurs without severe cortical neuronal losses.
Objective To advance our understanding of the natural history of A in neurodegenerative diseases.
Design We evaluated the expression of Ax-40 and Ax-42 in DLB using monoclonal antibodies and immunohistochemical techniques in 5 brain regions. The data were compared with those elicited with normal aging and from patients with AD.
Setting and Patients A postmortem study involving 19 patients with DLB without concurrent neuritic degeneration, 10 patients with AD, and 17 aged persons without dementia for control subjects.
Results The A plaques were more numerous in patients with DLB than in controls in most brain regions, although the Ax-42 plaque subtype was predominant in both conditions. Overall, Ax-42 plaque density was similar in patients with DLB and those with AD, but Ax-40 plaques were more numerous in persons with AD than in those with DLB. The ratio of Ax-40 to Ax-42 plaques was significantly reduced in persons with DLB compared with patients with AD.
Conclusions The A plaques were more numerous in patients with DLB than persons with normal aging, but the plaque subtypes were similar. The relative proportion of the 2 A plaque subtypes in DLB is distinguishable from that in AD.
INTRODUCTION
THE MOLECULAR basis of neuronal degeneration in Alzheimer disease (AD) is not fully understood, but recent attention1-14 has focused on the importance of the role of different-length -amyloid (A) peptides. Because there is an increased amount of the subtype Ax-42, but not of Ax-40,9 in presymptomatic patients with genetic forms of AD, including Down syndrome and presenilin 1 AD, Ax-42 deposition is considered12 an early event in the AD process, with Ax-40 plaques occurring later. Both A subtypes are present in the brains of older patients with Down syndrome and in patients with AD.9, 13-15
The biological factors associated with the accumulation of the different A subtypes in degenerative diseases are not well understood. Brain specimens from patients with familial AD, however, show greater amounts of Ax-42 than do those from patients with sporadic AD.13-15 Compared with that in patients with sporadic AD, the ratio of Ax-42 to Ax-40 is also increased in patients with AD with mutations of the amyloid precursor protein (APP) on chromosome 21 and presenilin 1 mutations on chromosome 14.13-15
Recent evidence16-17 suggests that intraneuronal organelles are important in the A cascade and in the formation of the A subtypes. The subtypes Ax-42 and Ax-40 are formed in the endoplasmic reticulum and the Golgi apparatus, respectively.16-17 Despite these major breakthroughs, the biological trigger for the A cascade is unknown. Also unknown is whether the process of A formation from APP involves an identical biochemical sequence of events in all A-forming diseases.
The study of A in other degenerative diseases may advance our understanding of the role of A in AD and in neuronal degeneration. Dementia with Lewy bodies (DLB) is an increasingly recognized18-21 subtype of dementia. Although DLB frequently occurs concurrently with AD changes, many patients have pure DLB.22 In patients with DLB not meeting pathological criteria for AD, A plaque (AP) deposition in the cortex is often increased compared with that in age-matched controls.23 In patients with DLB, however, cortical neuronal loss is minimal.24-26 Differences in Ax-40 and Ax-42 formation between AD and DLB suggest that the biochemical processes that lead to A formation may differ. To address this issue, we examine the relationship between DLB, AD, normal aging, and the different lengths of A.
PARTICIPANTS AND METHODS
PATIENTS WITH DLB
We examined the brains of 19 patients (mean age, 75.0 years at death) (Table 1) who met consensus pathological criteria27 for transitional or neocortical DLB. Specimens from 12 patients were obtained from the Neurology Brain Bank, MCP-Hahnemann University, Philadelphia, Pa, and specimens from 7 patients were obtained from the Department of Pathological Sciences University of Manchester, Manchester, England. Neurons were identified as containing Lewy bodies if inclusions had the morphologic appearance of a Lewy body and a nucleus was present. Cases were identified using hematoxylin-eosin stains and confirmed using ubiquitin and  -synuclein immunohistochemical stains. This group of patients had a varying number of diffuse APs shown by A immunohistochemical techniques and silver stains (described later). The brain specimens lacked other notable neuropathological features; in particular, they did not contain cortical neurofibrillary tangles. All had infrequent plaques by criteria of the consortium on DLB international workshop,28 and Braak stages29 ranged from I to IV. Most would be categorized as having a low likelihood that their dementia is caused by AD.30 No patients with DLB met criteria of the National Institute on Aging and the Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease30 for a high likelihood that dementia was related to AD. Although parkinsonism developed in some patients, all patients with DLB had dementia as the first symptom. No other notable neurologic diagnoses were identified. The mean duration of disease was 7.6 years, and all patients but 1 MCP-Hahnemann University case had advanced dementia, were in nursing homes, and required assistance for all activities before death. The other patient had moderate disease severity at death. The disease severity was not known for the 7 patients from the University of Manchester.
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Table 1. Clinical Features of 29 Patients With Dementia and 17 Control Subjects*
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PATIENTS WITH AD
We examined brain specimens from 10 patients from MCP-Hahnemann University, Philadelphia, who met clinical criteria of the National Institute of Neurological Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association31 for possible or probable AD. All had frequent neuritic plaque scores according to criteria of the Consortium to Establish a Registry for Alzheimer's Disease28 and Braak29 stages V or VI. All met criteria of the National Institute on Aging–Reagan Institute Working Group30 for a high likelihood that their dementia was related to AD. All patients lacked intracortical or nigral Lewy bodies. The mean age was 74.5 years at death. The mean disease duration was slightly longer in patients with AD (9.5 years) than in those with DLB, but these differences were not significant (P=.29). All except 1 patient died with advanced disease. This patient had moderately severe manifestations of the disease at death. None had significant concurrent neurologic diagnoses.
CONTROL SUBJECTS
We examined brain tissue from 17 control subjects who died without significant dementia or neuropathologic diagnoses. Cognitive status was confirmed by medical records review. The mean age at death was 75.9 years. Braak29 stages were I or II, and staging according to the consortium on DLB international workshop28 showed that neuritic plaques were infrequent. None had cortical or nigral Lewy bodies.
GENOTYPING
Genotyping for APOE was performed on brain tissue using a polymerase chain reaction protocol.32
NEUROPATHOLOGIC METHODS
We obtained coronal sections of the middle frontal gyrus, medial temporal lobe (CA1 and CA3 sectors of the hippocampus and parahippocampal gyrus [PHG]) at the level of the lateral geniculate nucleus, and cerebellar hemisphere lateral to the dentate gyrus. Tissue blocks were embedded in paraffin and cut to a thickness of 6 µm.
ANTIBODY PREPARATION AND STAINING
Sections were stained with antibodies directed against Ax-40 (6A; monoclonal, 1:1000 dilution) and Ax-42 (11C; monoclonal, 1:1000 dilution). Both antibodies—produced using standard methods—are C-terminal specific. Briefly, BALB/c mice (Japan SLC, Shizuoka, Japan) were immunized with the synthetic peptides with the sequence of either CVGGVV or CGVVIT, which corresponded to A36-40 or A38-42. The aminoterminal cysteine was added to the synthetic peptides for conjugation with keyhole limpet hemocyanin (Wako Chemicals, Osaka, Japan). After several immunizations, spleen lymphocytes from the immunized mice were fused with myeloma cells to generate the hybridoma. Following 2 limited dilution series, we screened the 2 monoclonal antibodies 6A and 11C for specificity by enzyme-linked immunosorbent assays using relevant synthetic peptides14 and Western blot analysis (Figure 1). Western blot specimens included 001, a rabbit polyclonal antibody against the A1-42 peptide, and a monoclonal antibody (2Fi) directed against A18-28, in addition to the 6A and 11C antibodies. These antibodies recognize both Ax-40 and Ax-42 species. A total of 100 ng of peptides was used for each lane. Sodium dodecyl sulfate polyacrylamide gel electrophoresis was carried out under reducing conditions on all specimens, and proteins on gels were transferred on PVDF membrane (Hybond-P, Amersham Life Sciences, United Kingdom). The membrane was blocked with 3% gelatin and incubated with the monoclonal antibody, followed by the horseradish peroxidase–conjugated second antibody. The color was developed with 4-chloro-1-naphthol. The protein concentration was quantitated by measuring the absorption at 562 nm using an assay kit (BCA, Pierce, Rockford, Ill).
In addition, each antibody was examined for the appropriate pattern of immunoreactivity using immunohistochemical technique on paraffin sections of brain from patients with AD. We used the biotin-streptavidin technique with diaminobenzidine and a light hematoxylin counterstain. All sections were pretreated with formic acid. Tissue designated "negative control" included adjacent sections where nonimmune serum replaced the primary antibodies. Tissue designated "positive control" included the cerebral cortex of patients with advanced AD known to have an abundance of both Ax-40 and Ax-42.
QUANTITATIVE METHODS
All A data were obtained by 2 observers (C.F.L. and Brendan O'Connell) who were blinded to the subjects' diagnosis during data acquisition. We obtained data from the middle frontal gyrus, the hippocampal CA1 and CA3 regions, the PHG, and the cerebellar hemisphere. To make our data comparable to those of other A studies, we measured AP densities and calculated the percentage of area with A (amyloid burden) from the field with the maximal AP deposition within each region of interest.8, 14 For density data, all APs at least as large as a small neuron were counted at a magnification of x10. Each field was 3.5 mm2. Densities in each region of interest were expressed as the number per square millimeter.
To determine the amyloid burden, we used a previously described sampling procedure33 but captured images using a digital camera (SenSys; Photometrics Ltd, Munich, Germany) attached to a light microscope (Precision Instrument Division, Olympus Corporation, Lake Success, NY). The percentage of each field stained by A was calculated using a semiautomated computer program (Image-Pro; Media Cybernetics, Silver Spring, Md) and sampling 0.6-mm2 fields.
For each specimen, the Ax-40:Ax-42 ratio was calculated in each region using both A sampling methods.
STATISTICAL ANALYSIS
Data were analyzed using an analysis of variance. Data differences that were significant at the P .05 level were further analyzed using the Tukey-Kramer method to determine which groups differed from each other. This method adjusts the P value to allow for multiple comparisons.
RESULTS
AP DENSITIES
Microscopic examination in affected regions showed that the A antibodies detected APs in regions consistent with their known distribution in AD. The subtype Ax-42 was common in all patients with AD and all patients with DLB except 1 but was more variable in controls. The same brain regions were preferentially affected in all groups, with the greatest number of APs in the frontal cortex, the fewest number in the PHG (CA sectors), and the lowest number in the cerebellum. In patients with DLB, Ax-42 plaques sometimes appeared smaller and more irregular than those observed in patients with AD. As expected, our Ax-40 antibody stained fewer APs than the Ax-42 antibody. Overall, Ax-40 was rare in control specimens and those from patients with DLB and variable in patients with AD. In addition to AP, patients with AD showed Ax-40 immunostaining of meningeal and intraparenchymal blood vessels.
When Ax-40 densities were compared (Table 2), overall differences were significant between control specimens (Figure 2, A), specimens from patients with DLB (Figure 2, C) and those from patients with AD (Figure 2, E) in all regions except the cerebellum. The F scores revealed that the group with AD had greater Ax-40 plaque densities than either the DLB group or the control group. In the cerebellum, statistical analysis was not possible because Ax-40 was absent in both the control group and the group with DLB (no variance within groups).
Overall, the Ax-40 burden (percentage of cortex with Ax-40 immunoreactivity) paralleled Ax-40 density data, with Ax-40 densities being less in controls and patients with DLB than in patients with AD. These differences reached significance in all regions except the cerebellum.
The Ax-42 plaque densities showed overall differences among controls (Figure 2, B), patients with DLB (Figure 2, D), and patients with AD (Figure 2, F), with the groups with DLB and AD showing greater densities of Ax-42 plaques than controls. In the frontal gyrus, CA3, and PHG, significant differences were observed among the 3 groups, with the group with DLB having Ax-42 plaque densities intermediate between those of the group with AD and controls. In the CA1 region, the control group had significantly fewer plaques than either of the other 2 groups. Differences between patients with AD and those with DLB were not significant in CA1. In the cerebellum, the group with AD showed greater densities than the group with DLB or the control group.
The Ax-42 burden also showed overall differences among the 3 groups. The control group showed a lower burden than the group with DLB, and the group with DLB showed less Ax-42 than the group with AD in all regions except the cerebellum, where the group with AD had greater Ax-42 burden than either of the other groups.
The Ax-40:Ax-42 ratio in all regions was significantly greater in the group with AD than in either the group with DLB or controls, whether density or amyloid burden was assessed (Figure 3 and Table 3). The Ax-40:Ax-42 ratio of the group with DLB was sometimes less than that of the control group, although these differences did not reach significance because of the small amount of Ax-40 in each group. In the cerebellum, ratios were 1.0 for the group with DLB and the control group and approached 0 for the group with AD because Ax-40 plaques are exceedingly rare in the cerebellum, even in persons with advanced AD.
APOE GENOTYPE
In most regions, patients with DLB (n=9) and those with AD (n=6) with the APOE  4 allele had similar densities and percentage of area with AP deposition compared with those lacking this allele (n=9 and n=4, respectively). In the control group, only 1 subject had the APOE 4 allele. In patients with DLB, differences between groups with and without APOE 4 varied, reaching significance in the PHG, where Ax-40 densities were 23.7/mm2 and 58.7/mm2, respectively (t1=2.809, P=.01). In patients with AD, the APOE genotype influenced Ax-40 deposition more consistently, with mean Ax-40 densities consistently greater in the group with AD with the 4 allele than in those without the 4 allele. These differences in Ax-40 deposition reached significance in sections from the CA1 and the PHG (4.86/mm2 and 16.97/mm2 [t=2.726, P=.03] vs 1.54/mm2 and 18.68/mm2 [t=2.377, P=.04], respectively). The presence of Ax-42 was not associated with increased AP deposition.
COMMENT
We confirmed previous reports that patients with DLB, those with AD, and control subjects have APs. We extend this finding by determining that the pattern of AP deposition differs between those with DLB and AD in all brain regions examined. In patients with DLB, Ax-40 plaque densities were less than the densities in patients with AD. The Ax-42 plaque densities were nearly as great in patients with DLB as they were in those with AD. Therefore, the Ax-40:Ax-42 ratio was less in patients with DLB than that in patients with AD. Also, the specimens of brain from patients with DLB lacking significant neuritic degeneration and severe neuronal losses contain increased densities of APs compared with age-matched controls. The pattern of AP deposition, however, is similar in normal aging and in patients with DLB, with almost all APs being composed of Ax-42; Ax-40 plaques were nearly nonexistent.
Why the Ax-40:Ax-42 ratio in patients with DLB differs from that in patients with AD is unknown. Our observation that Ax-40 densities in patients with DLB are less than those in patients with AD suggests that differences may occur between these 2 conditions in APP metabolism. We found no evidence to support the notion, however, that regional differences exist in the susceptibility to AP formation in these 2 conditions because the regional distribution of AP of both subtypes was similar in patients with AD and those with DLB. For example, in both conditions, the lowest density of APs (of either subtype) was found in the cerebellum, followed by the CA hippocampal subregions. The largest number of both Ax-40 and Ax-42 plaques was found in the cerebral cortex in patients with DLB and those with AD. Furthermore, the differences in Ax-40:Ax-42 ratios between patients with AD and those with DLB are not limited to specific brain regions.
The APOE genotype affects the likelihood of AD developing. Persons carrying the APOE 4 allele are more likely to acquire AD, and symptoms are more likely to develop at an earlier age34-35 than in those lacking this allele. In patients with AD, APOE affects the deposition of Ax-40 and not Ax-42.36 Our data from patients with AD confirm this trend. In our study, however, the effect of the APOE genotype was less marked in patients with DLB than in those with AD. The overall poor relationship between the APOE genotype and A in individual patients with DLB may be due to the paucity of Ax-40 plaques in those with DLB. When group trends are examined, however, the frequency of the 4 allele and the number of Ax-40 plaques are lower in the group with DLB than in the group with AD. Therefore, our data do not contradict the hypothesis that APOE principally affects Ax-40.
The relationship between in vivo neurotoxicity and A subtypes remains unknown. We postulate that the subtype of A deposited may be related to neuronal cell death. Many investigators think that Ax-42 is the more toxic and aggressive form of A because brain tissue from patients with early-onset AD (from both presenilin 1 and APP mutations) shows a reduced ratio of Ax-40: Ax-42.13-15 Patients with AD who have both presenilin 1 and APP have more severe neuronal losses and at an earlier age than comparable patients with late-onset AD.24-25,33 Our data are more compatible with the hypothesis that Ax-42 is benign and that Ax-40 (or the intraneuronal processes that contribute to Ax-40 formation) is more strongly associated with neuronal degeneration. A previous study26 reported that cortical neuronal loss is small in patients with DLB compared with the severe losses seen in those with AD. If Ax-42 exerts a major, direct neurotoxic effect, we would expect to find much lower levels of Ax-42 in the brain specimens of patients with DLB. Our immunohistochemical data from patients with DLB suggest that neuronal degeneration may occur after a threshold of Ax-40 is reached. Any effect from differences in the aminoterminal of A cannot be addressed by this study because the antibodies we used were specific only for the carboxyterminal.
The factors determining the relative proportion of Ax-40 to Ax-42 formed at the time of the metabolic breakdown of APP are not well understood. The subtypes Ax-40 and Ax-42 are both produced in the neuron during the metabolic degradation of APP.16-17 Cell culture studies by Hartmann et al16 and Cook et al17 suggest that Ax-42 synthesis occurs in the endoplasmic reticulum, whereas Ax-40 is produced at a more distal point in the Golgi apparatus. Further characterization of these intraneuronal events will be important for our understanding of the role of A in neuronal degeneration.
Recently, endoplasmic reticulum–associated A protein (ERAB) has been shown37 to bind Ax-42 in patients with AD. This protein may be crucial to the pathogenesis of AD because ERAB is overexpressed in the brain of patients with AD. In addition, cell culture studies show that the toxic effect of A on neurons is reduced when ERAB is blocked and increased when ERAB is overexpressed. The levels of ERAB in patients with DLB have not been determined. Because increased ERAB levels are associated with increased A neurotoxicity, however, ERAB may not be increased in patients with DLB as neuronal losses in such patients are small.
Dickson et al23 have termed patients with DLB with diffuse AP deposition as having pathological aging. Although the patients with DLB in this study do not meet consensus criteria30 for a high likelihood that their symptoms were due to AD, it could be argued that the increased amount of A indicates that they are in an early stage of the AD process and thus had incipient AD. Our data cannot determine whether A deposition is fundamentally different between patients with AD and those with DLB or whether plaque formation is in an earlier stage of AD, particularly because our patients with DLB had slightly shorter disease durations than the group with AD. Another study38 of AP deposition in patients with DLB that examined frontal cortex showed a similar trend. The near absence, however, of Ax-40 in patients with Ax-42 densities approaching those of patients with AD suggests that the events leading to A deposition in patients with AD and those with DLB may differ. Further study of factors determining which APP metabolite is formed in patients with DLB, those with AD, and as a result of normal aging may advance our understanding of the natural history of APP and A in neurodegenerative diseases.
AUTHOR INFORMATION
Accepted for publication December 11, 1998.
This study was supported in part by grant 13623 from the National Institute on Aging, Bethesda, Md, and the Robert Potamkin Fund (Dr Lippa). We acknowledge Brendan O'Connell for assistance with data acquisition, the Joseph and Kathleen Bryan Brain Bank at Duke University Medical Center, Durham, NC, which is supported by grant AG05128 from the National Institute on Aging and Glaxo Wellcome Inc, Research Triangle Park, NJ. We also acknowledge the Grant in Aid for Scientific Research on Priority Area (Dr Mori).
Reprints: Carol F. Lippa, MD, Department of Neurology, MCP-Hahnemann University, 3300 Henry Ave, Philadelphia, PA 19129 (e-mail: lippa{at}auhs.edu).
From the Department of Neurology, MCP-Hahnemann University, Philadelphia, Pa (Dr Lippa); Department of Neuroscience, Osaka City University Medical School, Aebnoku, Japan (Drs Ozawa, Ishii, Arawaka, and Mori) Division of Molecular Pathology, Department of Pathological Sciences, University of Manchester, Manchester, England (Dr Mann); and Division of Neuropathology, Department of Pathology, University of Massachusetts Medical Center, Worcester (Dr Smith).
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