Modified amyloid variants in pathological subgroups of <i>β</i>‐amyloidosis

Gerth, Janina; Kumar, Sathish; Upadhaya, Ajeet Rijal; Ghebremedhin, Estifanos; Arnim, Christine von; Thal, Dietmar Rudolf; Walter, Jochen

doi:10.1002/acn3.577

Cited by 23 publications

(60 citation statements)

References 65 publications

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“…Another, argument for a link between hypertension-related cardiac pathology and CAA is the finding of Gerth et al . that a distinct group of CAA cases based upon the parenchymal/vascular distribution pattern of modified Aβ forms was associated with arterial hypertension 41 . These results from other studies further support the hypothesis that hypertension-related lesions of the heart and CAA are linked.…”

Section: Discussionmentioning

confidence: 94%

Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis

Krämer

Brettschneider

Lennerz

et al. 2018

Sci Rep

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Cardiomyopathies with intracellular inclusions are a distinct subset of cardiomyopathies whereas basophilic degeneration (BD) of the heart describes inclusions in cardiomyocytes of the aging heart, which have not yet been related to a specific disease condition or to a distinct type of protein inclusion. To address the question whether BD represents a specific pathological feature and whether it is linked to a distinct disease condition we studied 62 autopsy cases. BD inclusions exhibited an immunohistochemical staining pattern related to glycosylated, δ- or η-secretase-derived N-terminal cleavage products of the amyloid precursor protein (sAPPδ/η) or shorter fragments of sAPPη. BD aggregates were found in the myocardium of both ventricles and atria with highest amounts in the atria and lowest in the interventricular septum. The frequency of BD-lesions correlated with age, degree of myocardial fibrosis in individuals with arterial hypertension, and the severity of cerebral amyloid angiopathy (CAA). The intracytoplasmic deposition of N-terminal sAPPδ/η fragments in BD indicates a specific inclusion body pathology related to APP metabolism. The correlation with the severity of CAA, which is related to the APP-derived amyloid β-protein, supports this point of view and suggests a possible link between myocardial and cerebrovascular APP-related lesions.

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Section: Discussionmentioning

confidence: 94%

Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis

Krämer

Brettschneider

Lennerz

et al. 2018

Sci Rep

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“…The Aβ peptide can undergo several post-translational modifications resulting, e.g., in truncated pyroglutamate Aβ (Aβ N3pE ) and Aβ phosphorylated at serine 8 (pSer8Aβ) [30][31][32]. These different Aβ isoforms are associated with clinical disease progression and are considered to mark sequential phases of plaque and CAA maturation [20,43,52].…”

Section: Introductionmentioning

confidence: 99%

The coarse-grained plaque: a divergent Aβ plaque-type in early-onset Alzheimer’s disease

et al. 2020

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Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque’s association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aβ-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque’s neuritic component (pTau, APP, PrPC), Aβ isoform composition (Aβ40, Aβ42, AβN3pE, pSer8Aβ), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aβ40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aβ40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aβ plaque-type associated with EOAD. Differences in Aβ processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aβ deposits. Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

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“…We recently showed that Aβ undergoes phosphorylation at serine residue 8, which affects its conformation, aggregation, neurotoxicity and proteolytic degradation [18,25,27,37,38]. Phosphorylated Ser8-Aβ (pSer8Aβ) occurs in vivo in the brains of human AD patients, nonhuman primates and canines [39][40][41][42]. Notably, the detection of pSer8Aβ, together with pyroglutamate modified Aβ in brain sections or brain extracts has recently been explored to establish a staging system for AD pathology based on the sequential deposition of these modified Aβ variants during the pathogenesis of AD [42].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

Kumar

Lemere

Walter

2020

acta neuropathol commun

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The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer's disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of Aβ deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified Aβ peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified Aβ species has been explored to characterize distinct stages of AD, with phosphorylated Aβ being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of Aβ caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated Aβ species in human DS, AD, and control brains. In addition, deposition of these Aβ species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific Aβ antibodies. Significant amounts of Aβ phosphorylated at serine residue 8 (pSer8Aβ) and unmodified Aβ were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct agedependent and spatiotemporal deposition of pSer8Aβ in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated Aβ species in DS brains, further supporting the similarity of Aβ deposition in AD and DS. Thus, the detection of phosphorylated and other modified Aβ species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of Aβ variants in AD and DS as well as in distinct mouse models.

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Modified amyloid variants in pathological subgroups of β‐amyloidosis

Cited by 23 publications

References 65 publications

Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis

Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis

The coarse-grained plaque: a divergent Aβ plaque-type in early-onset Alzheimer’s disease

Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

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