Aβ Seeding as a Tool to Study Cerebral Amyloidosis and Associated Pathology

Friesen, Marina; Meyer‐Luehmann, Melanie

doi:10.3389/fnmol.2019.00233

Cited by 35 publications

(30 citation statements)

References 142 publications

(215 reference statements)

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“…Aβ oligomers exert neurotoxicity, and oligomer levels correlate with neuronal dysfunction in AD [ 3 , 21 , 50 , 56 , 57 , 62 , 80 ]. Aβ oligomers also seed fibrillization and promote the deposition in form of extracellular plaques [ 6 , 10 , 20 , 32 ]. In addition, oligomers can be internalized by neurons resulting in Aβ accumulation within neurons [ 2 , 9 , 13 , 56 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits

Joshi

Riffel

Kumar

et al. 2021

acta neuropathol commun

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Progressive accumulation of Amyloid-β (Aβ) deposits in the brain is a characteristic neuropathological hallmark of Alzheimer’s disease (AD). During disease progression, extracellular Aβ plaques undergo specific changes in their composition by the sequential deposition of different modified Aβ species. Microglia are implicated in the restriction of amyloid deposits and play a major role in internalization and degradation of Aβ. Recent studies showed that rare variants of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are associated with an increased risk for AD. Post-translational modifications of Aβ could modulate the interaction with TREM2, and the uptake by microglia. Here, we demonstrate that genetic deletion of TREM2 or expression of a disease associated TREM2 variant in mice lead to differential accumulation of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits. Human brains with rare TREM2 AD risk variants also showed altered deposition of modified Aβ species in the different brain lesions as compared to cases with the common variant of TREM2. These findings indicate that TREM2 plays a critical role in the development and the composition of Aβ deposits, not only in extracellular plaques, but also intraneuronally, that both could contribute to the pathogenesis of AD.

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Section: Discussionmentioning

confidence: 99%

TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits

Joshi

Riffel

Kumar

et al. 2021

acta neuropathol commun

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“…Moreover, this imaging modality could be instrumental in studying the prion-like properties of Aβ fibrillar aggregates. Typical experiments involve exogenously inoculated Aβ seeds (prion-like agents) which template and accelerate Aβ deposition in the host brain [25,26]. Hence non-destructive 3D imaging would be a great advantage in identifying the spreading routes of inoculated seeds [27].…”

Section: Discussionmentioning

confidence: 99%

Brain virtual histology with X-ray phase-contrast tomography Part II: 3D morphologies of amyloid-β plaques in Alzheimer’s disease models

Chourrout

Roux

Boisvert

et al. 2021

Preprint

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While numerous transgenic mouse strains have been produced to model the formation of amyloid-β (Aβ) plaques in the brain, efficient methods for whole-brain 3D analysis of Aβ deposits are lacking. Moreover, standard immunohistochemistry performed on brain slices precludes any shape analysis of Aβ plaques. The present study shows how in-line (propagation-based) X-ray phase-contrast tomography (XPCT) combined with ethanol-induced brain sample dehydration enables hippocampus-wide detection and morphometric analysis of Aβ plaques. Performed in three distinct Alzheimer mouse strains, the proposed workflow identified differences in signal intensity and 3D shape parameters: 3xTg displayed a different type of Aβ plaques, with a larger volume and area, greater elongation, flatness and mean breadth, and more intense average signal than J20 and APP/PS1. As a label-free non-destructive technique, XPCT can be combined with standard immunohistochemistry. XPCT virtual histology could thus become instrumental in quantifying the 3D spreading and the morphological impact of seeding when studying prion-like properties of Aβ aggregates in animal models of Alzheimer's disease. This is Part II of a series of two articles reporting the value of in-line XPCT for virtual histology of the brain; Part I shows how in-line XPCT enables 3D myelin mapping in the whole rodent brain and in human autopsy brain tissue.

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“…Nevertheless, amyloid plaques in general first appear in the neocortex from where they spread into the allocortex and the subcortical regions (Thal et al, 2002 ; Serrano-Pozo et al, 2011 ; Grothe et al, 2017 ). As has been described above for tau, several studies on intracerebral injections of Aβ-rich brain extracts either from AD mice or patients propose that Aβ aggregation can be initiated by prion-like seeding (Kane et al, 2000 ; Meyer-Luehmann et al, 2006 ; Eisele et al, 2009 ; Jucker and Walker, 2013 ; Ziegler-Waldkirch et al, 2018 ; Friesen and Meyer-Luehmann, 2019 ; Katzmarski et al, 2020 ). These misfolded protein assemblies act as seeds of aggregation to accelerate the polymerization processes of normal proteins (Harper and Lansbury, 1997 ) that can expand from the injection site to distant regions as well as the contro-lateral side of the brain, thus suggesting a possible spread of seeded pathology via neuronal transport along axonally interconnected brain regions (Walker et al, 2002 ; Rönnbäck et al, 2012 ; Domert et al, 2014 ; Ye et al, 2015 ).…”

Section: The Spread Of Aβmentioning

confidence: 95%

Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer’s Disease

d’Errico

Meyer‐Luehmann

2020

Front. Aging Neurosci.

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117

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Alzheimer's disease (AD) is pathologically defined by extracellular accumulation of amyloid-β (Aβ) peptides generated by the cleavage of amyloid precursor protein (APP), strings of hyperphosphorylated Tau proteins accumulating inside neurons known as neurofibrillary tangles (NFTs) and neuronal loss. The association between the two hallmarks and cognitive decline has been known since the beginning of the 20th century when the first description of the disease was carried out by Alois Alzheimer. Today, more than 40 million people worldwide are affected by AD that represents the most common cause of dementia and there is still no effective treatment available to cure the disease. In general, the aggregation of Aβ is considered an essential trigger in AD pathogenesis that gives rise to NFTs, neuronal dysfunction and dementia. During the process leading to AD, tau and Aβ first misfold and form aggregates in one brain region, from where they spread to interconnected areas of the brain thereby inducing its gradual morphological and functional deterioration. In this mini-review article, we present an overview of the current literature on the spreading mechanisms of Aβ and tau pathology in AD since a more profound understanding is necessary to design therapeutic approaches aimed at preventing or halting disease progression.

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Aβ Seeding as a Tool to Study Cerebral Amyloidosis and Associated Pathology

Cited by 35 publications

References 142 publications

TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits

TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits

Brain virtual histology with X-ray phase-contrast tomography Part II: 3D morphologies of amyloid-β plaques in Alzheimer’s disease models

Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer’s Disease

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