Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome
Line De Kimpe,Elise S. van Haastert,Archontia Kaminari,Rob Zwart,Helma Rutjes,Jeroen J.M. Hoozemans,Wiep Scheper +6 more
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TLDR
The results presented in this study support a model where Aβ pathology and aging converge, leading to accumulation of the degradation-resistant pE-modified Aβ in the lysosomes, lysOSomal dysfunction, and neurodegeneration.Abstract:
Deposition of aggregated amyloid beta (Aβ) is a major hallmark of Alzheimer’s disease (AD)—a common age-related neurodegenerative disorder. Typically, Aβ is generated as a peptide of varying lengths. However, a major fraction of Aβ peptides in the brains of AD patients has undergone posttranslational modifications, which often radically change the properties of the peptides. Aβ3(pE)-42 is an N-truncated, pyroglutamate-modified variant that is abundantly present in AD brain and was suggested to play a role early in the pathogenesis. Here we show that intracellular accumulation of oligomeric aggregates of Aβ3(pE)-42 results in loss of lysosomal integrity. Using a novel antibody specific for aggregates of AβpE3, we show that in postmortem human brain tissue, aggregated AβpE3 is predominantly found in the lysosomes of both neurons and glial cells. Our data further demonstrate that AβpE3 is relatively resistant to lysosomal degradation, which may explain its accumulation in the lysosomes. The intracellular AβpE3 aggregates increase in an age-dependent manner. The results presented in this study support a model where Aβ pathology and aging converge, leading to accumulation of the degradation-resistant pE-modified Aβ in the lysosomes, lysosomal dysfunction, and neurodegeneration.read more
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Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons
Sofia Söllvander,Elisabeth Nikitidou,Robin Brolin,Linda Söderberg,Dag Sehlin,Lars Lannfelt,Anna Erlandsson +6 more
TL;DR: The results suggest that astrocytes play a central role in the progression of Alzheimer’s disease, by accumulating and spreading toxic Aβ species.
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Cathepsin B in Neurodegeneration of Alzheimer’s Disease, Traumatic Brain Injury, and Related Brain Disorders
Vivian Hook,Vivian Hook,Michael Yoon,Charles Mosier,Gen Ito,Sonia Podvin,Brian P. Head,Robert A. Rissman,Anthony J. O’Donoghue,Gregory Hook +9 more
TL;DR: This review integrates findings of cathepsin B regulation in clinical biomarker studies, animal model genetic and inhibitor evaluations, structural studies, and lysosomal cell biological mechanisms in AD, TBI, and related brain disorders to implicate cathePSin B as a major contributor to these neuropathological changes and behavioral deficits.
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Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons
Adam P Gunn,Bruce X. Wong,Timothy Johanssen,James C. Griffith,Colin L. Masters,Ashley I. Bush,Kevin J. Barnham,James A. Duce,Robert A. Cherny +8 more
TL;DR: Aβ3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (Aβ(1–42), andPyroglutamate formation was additionally found to increase the relative efficiency of Aβ-dityrosine oligomer formation mediated by copper-redox cycling.
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APP/Aβ structural diversity and Alzheimer's disease pathogenesis.
Alex E. Roher,Tyler A. Kokjohn,Steven Clarke,Michael R. Sierks,Chera L. Maarouf,Geidy E. Serrano,Marwan S. Sabbagh,Thomas G. Beach +7 more
TL;DR: A systematic examination of A&bgr; PTM and the analysis of the toxicity that they induced may help create essential biomarkers to more precisely stage AD pathology, design countermeasures and gauge the impacts of interventions.
References
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Journal ArticleDOI
The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics
John Hardy,Dennis J. Selkoe +1 more
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Journal ArticleDOI
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
Christian Haass,Dennis J. Selkoe +1 more
TL;DR: Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.
Journal ArticleDOI
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
Rakez Kayed,Elizabeth Head,Jennifer L. Thompson,Theresa M. McIntire,Saskia Milton,Carl W. Cotman,Charles G. Glabe +6 more
TL;DR: It is shown that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomer regardless of sequence, suggesting they share a common mechanism of toxicity.
Journal ArticleDOI
Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations
Ju-Hyun Lee,Ju-Hyun Lee,W. Haung Yu,W. Haung Yu,Asok Kumar,Asok Kumar,Sooyeon Lee,Sooyeon Lee,Panaiyur S. Mohan,Panaiyur S. Mohan,Corrinne M. Peterhoff,Devin M. Wolfe,Marta Martinez-Vicente,Ashish C. Massey,Guy Sovak,Yasuo Uchiyama,David Westaway,Ana Maria Cuervo,Ralph A. Nixon,Ralph A. Nixon +19 more
TL;DR: It is shown that macroautophagy requires the Alzheimer's disease-related protein presenilin-1 (PS1) for v-ATPase targeting to lysosomes, lysOSome acidification, and proteolysis during autophagy, which represents a basis for pathogenic protein accumulations and neuronal cell death in AD.
Journal ArticleDOI
ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.
Paige E. Cramer,John R. Cirrito,Daniel W. Wesson,Daniel W. Wesson,C. Y. Daniel Lee,J. Colleen Karlo,Adriana E. Zinn,Brad T. Casali,Jessica L. Restivo,Whitney D. Goebel,Michael J. James,Kurt R. Brunden,Donald A. Wilson,Gary E. Landreth +13 more
TL;DR: Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner, and stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function.
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