N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease

Bayer, Thomas A.

doi:10.3389/fnagi.2021.710579

Cited by 10 publications

(5 citation statements)

References 95 publications

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“…The data presented here highlight the broad distribution of the different Aβ species among the amyloid and pre-amyloid deposits, demonstrating the presence of all peptide forms investigated—including the N-terminally cleaved fragments Aβ4-x—in plaques and CAA deposits. Notably and consistent with previous findings from our lab as well as the work of other groups, species starting at Phe4 are abundantly distributed and represent a dominant fraction in vascular deposits and cored plaques overlapping in many cases with the more fibrillar areas of the thioflavin-S-positive lesions [ 39 , 44 , 90 ].…”

Section: Discussionsupporting

confidence: 91%

N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology

Rostagno

Cabrera

Lashley

et al. 2022

Transl Neurodegener

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Background The molecular heterogeneity of Alzheimer’s amyloid-β (Aβ) deposits extends well beyond the classic Aβ1-40/Aβ1-42 dichotomy, substantially expanded by multiple post-translational modifications that increase the proteome diversity. Numerous truncated fragments consistently populate the brain Aβ peptidome, and their homeostatic regulation and potential contribution to disease pathogenesis are largely unknown. Aβ4-x peptides have been reported as major components of plaque cores and the limited studies available indicate their relative abundance in Alzheimer’s disease (AD). Methods Immunohistochemistry was used to assess the topographic distribution of Aβ4-x species in well-characterized AD cases using custom-generated monoclonal antibody 18H6—specific for Aβ4-x species and blind for full-length Aβ1-40/Aβ1-42—in conjunction with thioflavin-S and antibodies recognizing Aβx-40 and Aβx-42 proteoforms. Circular dichroism, thioflavin-T binding, and electron microscopy evaluated the biophysical and aggregation/oligomerization properties of full-length and truncated synthetic homologues, whereas stereotaxic intracerebral injections of monomeric and oligomeric radiolabeled homologues in wild-type mice were used to evaluate their brain clearance characteristics. Results All types of amyloid deposits contained the probed Aβ epitopes, albeit expressed in different proportions. Aβ4-x species showed preferential localization within thioflavin-S-positive cerebral amyloid angiopathy and cored plaques, strongly suggesting poor clearance characteristics and consistent with the reduced solubility and enhanced oligomerization of their synthetic homologues. In vivo clearance studies demonstrated a fast brain efflux of N-terminally truncated and full-length monomeric forms whereas their oligomeric counterparts—particularly of Aβ4-40 and Aβ4-42—consistently exhibited enhanced brain retention. Conclusions The persistence of aggregation-prone Aβ4-x proteoforms likely contributes to the process of amyloid formation, self-perpetuating the amyloidogenic loop and exacerbating amyloid-mediated pathogenic pathways.

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Section: Discussionsupporting

confidence: 91%

N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology

Rostagno

Cabrera

Lashley

et al. 2022

Transl Neurodegener

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“…In aqueous solution and in 10% sodium dodecyl sulfate micelles Aβ pE3-40 peptides showed increased β-sheet formation using CD spectroscopy and aggregation behavior by sedimentation analysis when compared with Aβ 1-40 [ 48 ]. The relative toxicity and abundance of N-truncated and full-length Aβ variants both in vitro and in vivo in AD mouse models was reviewed and discussed previously [ 21 , 49 – 51 ].…”

Section: Properties Of Pyroglutamate Aβmentioning

confidence: 99%

Pyroglutamate Aβ cascade as drug target in Alzheimer’s disease

Bayer

2021

Mol Psychiatry

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One of the central aims in Alzheimer’s disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work very well in preclinical model systems both in vitro and in vivo in AD mouse models. However, the lack of translation into clinical settings in the AD field is a challenging endeavor. Although it is long known that N-terminally truncated and pyroglutamate-modified Abeta (AβpE3) peptides are abundantly present in the brain of AD patients, form stable and soluble low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, their potential as drug target has not been generally accepted in the past. This situation has dramatically changed with the report that passive immunization with donanemab, an AβpE3-specific antibody, cleared aymloid plaques and stabilized cognitive deficits in a group of patients with mild AD in a phase II trial. This review summarizes the current knowledge on the molecular mechanisms of generation of AβpE, its biochemical properties, and the intervention points as a drug target in AD.

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“…In this work, the FITC tag can change the hydrophilic–hydrophobic balance of the peptides, can induce steric hindrance or may change the peptide conformation, leading to a lower propensity for aggregation. For instance, it was reported in the literature that the N‐terminally truncated amyloid peptides were more prone to aggregation than the full length ones [26–29] because the truncated peptides would become more hydrophobic, which supports that an increase in hydrophilicity at the N‐terminus region would impair the aggregation.…”

Section: Resultsmentioning

confidence: 98%

Taylor dispersion analysis discloses the impairment of Aβ peptide aggregation by the presence of a fluorescent tag

et al. 2022

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The use of fluorescently tagged amyloid peptides, implicated in Alzheimer's disease, to study their aggregation at low concentrations is a common method; however, the fluorescent tag should not introduce a bias in the aggregation process. In this work, native amyloid peptides Aβ(1–40) and Aβ(1–42) and fluorescein‐5‐isothiocyanate (FITC), tagged ones, were studied using Taylor dispersion analysis coupled with a simultaneous UV and light‐emitting diode‐induced fluorescence detection, to unravel the effect of FITC on the aggregation process. For that, a total concentration of 100 µM of peptides consisting of a mixture of native and tagged ones (up to 10% in moles) was applied. Results demonstrated that FITC had a strong inhibition effect upon the aggregation behaviour of Aβ(1–42), whereas for Aβ(1–40), only a retardation in kinetics was observed. It was also shown that when mixed solutions of Aβ(1–40) and Aβ(1–42) are used, the Aβ(1–42) alloform was the leading peptide in the aggregation process, and when the latter was tagged, the aggregation kinetics decreased but the lifetime of potentially toxic oligomers was drastically increased. These results confirmed that the hydrophilicity of the N‐terminus part of the peptide plays a major role in the aggregation process.

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N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease

Cited by 10 publications

References 95 publications

N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology

N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology

Pyroglutamate Aβ cascade as drug target in Alzheimer’s disease

Taylor dispersion analysis discloses the impairment of Aβ peptide aggregation by the presence of a fluorescent tag

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