Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein

Glenner, George G.; Wong, Caine W.

doi:10.1016/s0006-291x(84)80190-4

Cited by 4,772 publications

(2,610 citation statements)

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“…This most common type of dementia is characterized by progressive cognitive decline and two histopathological hallmarks including amyloid-beta (Αβ) plaques, which are caused by an imbalance in Aβ metabolism, and neurofibrillary tangles that result from abnormal phosphorylation and aggregation of Tau (Glenner and Wong, 1984;Grundke-Iqbal et al, 1986). Reelin binding to its receptors potently downregulates the activity of GSK3β, a major Tau kinase, and as a result mutant mice with defects in the Reelin signaling show increased levels of hyperphosphorylated Tau (Beffert et al, 2004;Hiesberger et al, 1999;Ohkubo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Age-related accumulation of Reelin in amyloid-like deposits

Knuesel

Nyffeler

Mormède

et al. 2009

Neurobiology of Aging

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Age-related accumulation of Reelin in amyloid-like deposits Abstract Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Abeta species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD. ABSTRACTAccumulating evidence suggest that alterations in Reelin-mediated signalling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits.These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Aβ species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD.3

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Section: Introductionmentioning

confidence: 99%

Age-related accumulation of Reelin in amyloid-like deposits

Knuesel

Nyffeler

Mormède

et al. 2009

Neurobiology of Aging

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“…Amyloid-beta (Aβ) peptides form the major component of amyloid plaques deposited in the brain of patients suffering from neurodegenerative diseases such as Alzheimer's disease (Glenner and Wong, 1984), dementia with Lewy bodies (DLB) (Jendroska et al ., 1997) and Parkinson's disease dementia (PDD) (Jendroska et al ., 1996). …”

Section: Introductionmentioning

confidence: 99%

CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

186

146

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As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (Aβ) peptides, such as Aβ1–42. Absolute Aβ1–42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based Aβ-sodium-dodecylsulphate–polyacrylamide-gel-electrophoresis with Western immunoblot (Aβ-SDS–PAGE/immunoblot) revealed a highly conserved Aβ peptide pattern of the carboxy-terminally truncated Aβ peptides 1–37, 1–38, 1–39 in addition to 1–40 and 1–42 in human CSF. We used the Aβ-SDS–PAGE/immunoblot to investigate the CSF of 23 patients with Alzheimer's disease, 21 with DLB, 21 with PDD and 23 non-demented disease controls (NDC) for disease-specific alterations of the Aβ peptide patterns in its absolute and relative quantities. The diagnostic groups were matched for age and severity of dementia. The present study is the first attempt to evaluate the meaning of Aβ peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases—Alzheimer's disease, DLB and PDD. The Aβ peptide patterns displayed disease-specific variations and the ratio of the differentially altered Aβ1–42 to the Aβ1–37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Aβ-like immunoreactivity was observed constantly in the CSF of all 88 investigated patients. The pronounced percentage increase of this peptide in DLB allowed a highly significant discrimination from PDD. Using a cut-off point of 0.954%, this marker yielded a diagnostic sensitivity and specificity of 81 and 71%, respectively. From several lines of indication, we consider this peptide to represent an oxidized α-helical form of Aβ1–40 (Aβ1–40*). The increased abundance of Aβ1–40* probably reflects a disease-specific alteration of the Aβ1–40 metabolism in DLB. We conclude that Aβ peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Aβ peptide patterns failed to fulfil the requirements for a sole biomarker, their combined evaluation with other biomarkers is promising in neurochemical dementia diagnosis. It is noteworthy that DLB and PDD exhibit distinct clinical temporal courses, despite their similar neuropathological appearance. Their distinct molecular phenotypes support the view of different pathophysiological pathways for each of these neurodegenerative diseases.

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“…The amyloid filaments are composed of 39-43 amino acid amyloid β (Aβ) peptides, which are derived from sequential proteolysis of amyloid precursor protein (APP) by β-secretase and γ-secretase [15,24,42]. While the β-secretase has been identified as an aspartyl protease called β-APP cleaving enzyme (BACE), recent data suggest that γ-secretase activity resides in a high molecular weight multimeric protein complex composed of at least four core components, i.e., presenilin 1 or 2 (PS1 or PS2), nicastrin, anterior pharynx defective-1 (APH-1) and presenilin enhancer-2 (PEN-2) [9,46,50].…”

Section: Introductionmentioning

confidence: 99%

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Kodam

Vetrivel

Wang

et al. 2008

Neurobiology of Aging

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Nicastrin and presenilin 1 are integral components of the high molecular weight γ-secretase complexes that regulate proteolytic processing of various type I membrane proteins including amyloid precursor protein and Notch. At present, there is little information regarding the cellular distribution of nicastrin in the developing or adult rat brain. We report here, using immunoblotting and immunohistochemical methods, that nicastrin in the adult rat brain is widely expressed and colocalized with presenilin 1 in select neuronal populations within all major areas, including the basal forebrain, striatum, cortex, hippocampus, amygdala, thalamus, hypothalamus, cerebellum and brainstem. We also observed dense neuropil labeling in many regions in the brain, suggesting that nicastrin gets transported to dendrites and/or axon terminals in the central nervous system. The levels of nicastrin are found to be relatively high at the early stages of postnatal development and then declined gradually to reach the adult profile. At the cellular level, nicastrin is localized predominantly in neuronal cell bodies at early postanatal stages, but is apparent both in cell bodies and dendrites/ neuropil in all brain regions at the later stages. The regulation of nicastrin expression and localization during development and its distribution in a wide spectrum of neurons in the postnatal and adult rat brains provide an anatomical basis to suggest a multifunctional role for the γ-secretase complex in the developing and adult rat brains.

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Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein

Cited by 4,772 publications

References 9 publications

Age-related accumulation of Reelin in amyloid-like deposits

Age-related accumulation of Reelin in amyloid-like deposits

CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

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