Cerebral vascular amyloid seeds drive amyloid β-protein fibril assembly with a distinct anti-parallel structure

Xu, Feng; Fu, Ziao; Dass, Sharmila; Kotarba, AnnMarie E.; Davis, James Earl; Smith, Steven O.; Nostrand, William E. Van

doi:10.1038/ncomms13527

Cited by 32 publications

(41 citation statements)

References 66 publications

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“…1, E and F) revealed that both F p␤ and F ␤ fibrils were rich in cross-␤ structures. The FT-IR spectra of both F ␤ and F p␤ fibrils showed main peaks at ϳ 1628 nm Ϫ1 that were also consistent with previous studies on A␤ fibrils (51)(52)(53). However, two spectra were distinct in the loop or turn regions between 1640 and 1680 cm Ϫ1 , indicating certain levels of structural variations between the two fibrils.…”

Section: Resultssupporting

confidence: 89%

Phosphorylation at Ser8 as an Intrinsic Regulatory Switch to Regulate the Morphologies and Structures of Alzheimer's 40-residue β-Amyloid (Aβ40) Fibrils

Chen

et al. 2017

Journal of Biological Chemistry

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Polymorphism of amyloid-β (Aβ) fibrils, implying different fibril structures, may play important pathological roles in Alzheimer's disease (AD). Morphologies of Aβ fibrils were found to be sensitive to fibrillation conditions. Herein, the Ser-phosphorylated Aβ (pAβ), which is assumed to specially associate with symptomatic AD, is reported to modify the morphology, biophysical properties, cellular toxicity, and structures of Aβ fibrils. Under the same fibrillation conditions, pAβ favors the formation of fibrils (F), which are different from the wild-type Aβ fibrils (F). Both F and F fibrils show single predominant morphologies. Compared with F, F exhibits higher propagation efficiency and higher neuronal cell toxicity. The residue-specific structural differences between the F- and F-seeded Aβ fibrils were identified using magic angle spin NMR. Our results suggest a potential regulatory mechanism of phosphorylation on Aβ fibril formation in AD and imply that the post-translationally modified Aβ, especially the phosphorylated Aβ, may be an important target for the diagnosis or treatment of AD at specific stages.

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Section: Resultssupporting

confidence: 89%

Phosphorylation at Ser8 as an Intrinsic Regulatory Switch to Regulate the Morphologies and Structures of Alzheimer's 40-residue β-Amyloid (Aβ40) Fibrils

Chen

et al. 2017

Journal of Biological Chemistry

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“…Furthermore, the site of leading A β maturation might attract further proteins to accumulate. This interpretation corresponds to the finding that seeds of A β aggregates could induce further A β deposition and argues in favor of the view that the presence of local seeds determines the aggregation pattern. However, it will be important to investigate whether the apparent maturation of A β in individual deposits results from addition of modified species to existing A β aggregates or whether already aggregated A β within deposits undergoes post‐translational modification.…”

Section: Discussionsupporting

confidence: 82%

Modified amyloid variants in pathological subgroups of β‐amyloidosis

Gerth

Kumar

Upadhaya

et al. 2018

Ann Clin Transl Neurol

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ObjectiveAmyloid β (Aβ) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post‐translationally modified Aβ in plaques characterizes distinct biochemical stages of Aβ maturation. However, the molecular composition of vascular Aβ deposits in CAA and its relation to plaques remain enigmatic.MethodsVascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated Aβ in the medial temporal and occipital lobe of 24 controls, 27 pathologically‐defined preclinical AD, and 20 symptomatic AD cases.ResultsSequential deposition of Aβ in CAA resembled Aβ maturation in plaques and enabled the distinction of three biochemical stages of CAA. B‐CAA stage 1 was characterized by deposition of Aβ in the absence of pyroglutaminated Aβ N3pE and phosphorylated Aβ pS8. B‐CAA stage 2 showed additional Aβ N3pE and B‐CAA stage 3 additional Aβ pS8. Based on the Aβ maturation staging in CAA and plaques, three case groups for Aβ pathology could be distinguished: group 1 with advanced Aβ maturation in CAA; group 2 with equal Aβ maturation in CAA and plaques; group 3 with advanced Aβ maturation in plaques. All symptomatic AD cases presented with end‐stage plaque maturation, whereas CAA could exhibit immature Aβ deposits. Notably, Aβ pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia.InterpretationBalance of Aβ maturation in CAA and plaques defines distinct pathological subgroups of β‐amyloidosis. The association of CAA‐related Aβ maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined Aβ pathology subgroups, and the subgroup‐related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention.

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“…in FTIR spectra that is characteristic of antiparallel structure of the b strands forming the backbone of the Ab fibrils. 33 This structure is distinct from the parallel registry observed in parenchymal plaque amyloid fibrils. 55,56 The b-sheet, antiparallel fibril character is also observed in the cerebral microvascular amyloid deposits of the rTg-DI rats (Figure 3).…”

Section: Discussionmentioning

confidence: 79%

“…Fibrils seeded from cerebral vascular amyloid exhibit intense FTIR bands characteristic of antiparallel b-strand structure. 33 Notably, the newly formed seeded wild-type Ab40 fibrils from rTg-DI microvascular amyloid exhibit a similar antiparallel signature, as reflected by the strong FTIR spectral band at approximately 1607/cm ( Figure 3I).…”

Section: Early-onset and Extensive Accumulation Of Cerebral Microvascmentioning

confidence: 84%

“…Fibrils seeded from the vascular amyloid isolated from rTg-DI rats exhibit intense bands in Fourier transform infrared (FTIR) spectra characteristic of antiparallel b-sheet, similar to that previously observed for human cerebral vascular amyloid. 33 Moreover, in rTg-DI rats, the cerebral microvascular Ab deposits cause capillary structural changes, promote prominent perivascular glial activation, and produce consistent, robust microhemorrhages with small-vessel occlusions that are readily detected by magnetic resonance imaging (MRI).…”

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confidence: 99%

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A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

Davis

Hatfield

et al. 2018

The American Journal of Pathology

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Accumulation of fibrillar amyloid b protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesis of this condition. Herein, we describe the generation and characterization of a novel transgenic rat (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant amyloid b protein in brain and faithfully recapitulates many of the pathologic aspects of human smallvessel CAA. rTg-DI rats exhibit early-onset and progressive accumulation of cerebral microvascular fibrillar amyloid accompanied by early-onset and sustained behavioral deficits. Comparable to CAA in humans, the cerebral microvascular amyloid in rTg-DI rats causes capillary structural alterations, promotes prominent perivascular neuroinflammation, and produces consistent, robust microhemorrhages and small-vessel occlusions that are readily detected by magnetic resonance imaging. The rTg-DI rats provide a new model to investigate the pathogenesis of small-vessel CAA and microhemorrhages, to develop effective biomarkers for this condition and to test therapeutic interventions. (Am J Pathol 2018, 188: 2877e2889; https://doi.

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Cerebral vascular amyloid seeds drive amyloid β-protein fibril assembly with a distinct anti-parallel structure

Cited by 32 publications

References 66 publications

Phosphorylation at Ser8 as an Intrinsic Regulatory Switch to Regulate the Morphologies and Structures of Alzheimer's 40-residue β-Amyloid (Aβ40) Fibrils

Phosphorylation at Ser8 as an Intrinsic Regulatory Switch to Regulate the Morphologies and Structures of Alzheimer's 40-residue β-Amyloid (Aβ40) Fibrils

Modified amyloid variants in pathological subgroups of β‐amyloidosis

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

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