scholarly journals BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo

2005 ◽  
Vol 168 (2) ◽  
pp. 291-302 ◽  
Author(s):  
Edward B. Lee ◽  
Bin Zhang ◽  
Kangning Liu ◽  
Eric A. Greenbaum ◽  
Robert W. Doms ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
Subcellular Location ◽  
Amyloid Plaque ◽  
Amyloid Deposition ◽  
Amyloid Formation ◽  
Aβ Peptides ◽  
Aβ Amyloid ◽  
Β Amyloid ◽  
The Relationship

Introducing mutations within the amyloid precursor protein (APP) that affect β- and γ-secretase cleavages results in amyloid plaque formation in vivo. However, the relationship between β-amyloid deposition and the subcellular site of Aβ production is unknown. To determine the effect of increasing β-secretase (BACE) activity on Aβ deposition, we generated transgenic mice overexpressing human BACE. Although modest overexpression enhanced amyloid deposition, high BACE overexpression inhibited amyloid formation despite increased β-cleavage of APP. However, high BACE expression shifted the subcellular location of APP cleavage to the neuronal perikarya early in the secretory pathway. These results suggest that the production, clearance, and aggregation of Aβ peptides are highly dependent on the specific neuronal subcellular domain wherein Aβ is generated and highlight the importance of perikaryal versus axonal APP proteolysis in the development of Aβ amyloid pathology in Alzheimer's disease.

scholarly journals New Biochemical Insights to Unravel the Pathogenesis of Alzheimer's Lesions

1991 ◽  
Vol 18 (S3) ◽  
pp. 408-410 ◽  
Author(s):  
Alex E. Roher ◽  
Kenneth C. Palmer ◽  
John Capodilupo ◽  
Arun R. Wakade ◽  
Melvyn J. Ball
Keyword(s):  
Amyloid Plaque ◽  
Extracellular Proteins ◽  
High Yield ◽  
Chemical Fractionation ◽  
Core Proteins ◽  
Β Amyloid ◽  
Neuritic Sprouting

ABSTRACT:Purification of amyloid plaque core proteins (APCP) from Alzheimer's disease brains to complete homogeneity and in high yield permitted its chemical fractionation and characterization of its components. APCP is mainly made of β-amyloid (βA) and an assortment of glycoproteins (accounting for 20%) rich in carbohydrates compatible with N-and O-linked saccharides. When added to tissue culture of sympathetic and sensory neurons APCP and βA inhibited neuritic sprouting, a reversible phenomenon at low doses. Higher concentrations of both substances kill the neurons in culture. APCP is significantly more toxic than βA, suggesting the minor components may play an important role in increasing the toxicity of βA. If the observed toxic effects of APCP in situ are occurring in vivo during the course of AD, then the accumulation of these extracellular proteins could be largely responsible for some of the neuronal death observed in this neuropathology.

IC-P2-149: In vivo assessment of β-amyloid deposition: A longitudinal study

2008 ◽  
Vol 4 ◽  
pp. T65-T65
Author(s):  
Victor L. Villemagne ◽  
Kerryn E. Pike ◽  
Uwe Ackermann ◽  
David Ames ◽  
Kathryn Ellis ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
Amyloid Deposition ◽  
Β Amyloid ◽  
In Vivo Assessment

P2-002: [18 F]BAY 94-9172 PET - Towards in vivo quantification of brain β-amyloid plaque load in Alzheimer disease

2009 ◽  
Vol 5 (4S_Part_9) ◽  
pp. P260-P260
Author(s):  
Osama Sabri ◽  
Henryk Barthel ◽  
Georg Becker ◽  
Julia Luthardt ◽  
Marianne Patt ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Plaque ◽  
Plaque Load ◽  
Β Amyloid

scholarly journals Serum Zinc Levels and in Vivo Beta-Amyloid Deposition in the Human Brain

2021 ◽  
Author(s):  
Jee Wook Kim ◽  
Min Soo Byun ◽  
Dahyun Yi ◽  
Jun Ho Lee ◽  
Min Jung Kim ◽  
...  
Keyword(s):  
Serum Zinc ◽  
Beta Amyloid ◽  
Zinc Level ◽  
Amyloid Deposition ◽  
Serum Zinc Level ◽  
Positron Emission ◽  
Zinc Levels ◽  
The Relationship ◽  
Serum Zinc Levels

Abstract Background: Despite the known associations between zinc levels and Alzheimer’s disease (AD) dementia and related cognitive impairment, the underlying neuropathological links remain poorly understood. We tested the hypothesis that serum zinc level is associated with cerebral beta-amyloid protein (Ab) deposition. Additionally, we explored associations between serum zinc levels and other AD pathologies [i.e., tau deposition and AD-signature cerebral glucose metabolism (AD-CM)] and white matter hyperintensities (WMHs), which are measures of cerebrovascular injury. Methods: A total of 241 cognitively normal older adults between 55 and 90 years of age were enrolled. All the participants underwent comprehensive clinical assessments, serum zinc level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Zinc levels were stratified into three categories: < 80 µg/dL (low), 80 to 90 µg/dL (medium), and > 90 µg/dL (high). Results: A low serum zinc level was significantly associated with increased Ab retention. In addition, apolipoprotein E ε4 allele (APOE4) status moderated the association: the relationship between low zinc level and Ab retention was significant only in APOE4 carriers. Although a low zinc level appeared to reduce AD-CM, the relationship became insignificant on sensitivity analysis including only individuals with no nutritional deficiency. The serum zinc level was associated with neither tau deposition nor the WMH volume. Conclusions: Our findings suggest that decreased serum zinc levels are associated with elevation of brain amyloid deposition. In terms of AD prevention, more attention needs to be paid to the role of zinc.

IC-P-113: [18 F]BAY 94-9172 PET: Towards in vivo quantification of brain β-amyloid plaque load in Alzheimer's disease

2009 ◽  
Vol 5 (4S_Part_2) ◽  
pp. P47-P47
Author(s):  
Osama Sabri ◽  
Henryk Barthel ◽  
Georg Becker ◽  
Julia Luthardt ◽  
Marianne Patt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaque ◽  
Plaque Load ◽  
Β Amyloid

scholarly journals Mechanism of cellular production and in vivo seeding effects of hexameric β-amyloid assemblies

2020 ◽  
Author(s):  
Céline Vrancx ◽  
Devkee M Vadukul ◽  
Sabrina Contino ◽  
Nuria Suelves ◽  
Ludovic D’Auria ◽  
...  
Keyword(s):  
Cell Lines ◽  
Amyloid Deposition ◽  
Amyloid Peptide ◽  
Intracerebral Injection ◽  
Cytotoxic Effects ◽  
Wide Range ◽  
Β Amyloid ◽  
5Xfad Mice

AbstractBackgroundThe β-amyloid peptide (Aβ) plays a key role in Alzheimer’s disease. After its production by catabolism of the amyloid precursor protein (APP) through the action of presenilin 1 (PS1)- or presenilin 2 (PS2)-dependent γ-secretases, monomeric Aβ can assemble in oligomers. In a pathological context, this eventually leads to the formation of fibrils, which deposit in senile plaques. Many studies suggest that Aβ toxicity is related to its soluble oligomeric intermediates. Among these, our interest focuses on hexameric Aβ, which acts as a nucleus for Aβ self-assembly.MethodsBiochemical analyses were used to identify hexameric Aβ in a wide range of models; cell lines, cerebrospinal fluid from cognitively impaired patients and transgenic mice exhibiting human Aβ pathology (5xFAD). We isolated this assembly and assessed both its effect on primary neuron viability in vitro, and its contribution to amyloid deposition in vivo following intracerebral injection. In both cases, we used wild-type mice (C57BL/6) to mimic an environment where hexameric Aβ is present alone and 5xFAD mice to incubate hexameric Aβ in a context where human Aβ species are pre-existing. Using CRISPR-Cas9, we produced stable knockdown human cell lines for either PS1 or PS2 to elucidate their contribution to the formation of hexameric Aβ.ResultsIn WT mice, we found that neither in vitro or in vivo exposure to hexameric Aβ was sufficient to induce cytotoxic effects or amyloid deposition. In 5xFAD mice, we observed a significant increase in neuronal death in vitro following exposure to 5μM hexameric Aβ, as well as a 1.47-fold aggravation of amyloid deposition in vivo. At the cellular level, we found hexameric Aβ in extracellular vesicles and observed a strong decrease in its excretion when PS2 was knocked down by 60%.ConclusionsOur results indicate the absence of cytotoxic effects of cell-derived hexameric Aβ by itself, but its capacity to aggravate amyloid deposition by seeding other Aβ species. We propose an important role for PS2 in the formation of this particular assembly in vesicular entities, in line with previous reports linking the restricted location of PS2 in acidic compartments to the production of more aggregation-prone Aβ.

99mTc-labeled dibenzylideneacetone derivatives as potential SPECT probes for in vivo imaging of β-amyloid plaque

2013 ◽  
Vol 64 ◽  
pp. 90-98 ◽  
Author(s):  
Yanping Yang ◽  
Mengchao Cui ◽  
Bing Jin ◽  
Xuedan Wang ◽  
Zijing Li ◽  
...  
Keyword(s):  
In Vivo Imaging ◽  
Amyloid Plaque ◽  
Β Amyloid

P1-285: First results toward in vivo quantification of cerebral β-amyloid plaque load in Alzheimer's disease by means of BAY 94-9172-PET

2008 ◽  
Vol 4 ◽  
pp. T301-T301
Author(s):  
Osama Sabri ◽  
Henryk Barthel ◽  
Marianne Patt ◽  
Eva Hammerstein ◽  
Georg Becker ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaque ◽  
Plaque Load ◽  
First Results ◽  
Β Amyloid

scholarly journals Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection

2020 ◽  
Vol 13 ◽  
Author(s):  
Madeleine R. Brown ◽  
Sheena E. Radford ◽  
Eric W. Hewitt
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Aβ Peptides ◽  
Aβ Amyloid ◽  
Aβ Fibrils ◽  
The Brain

Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease.

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