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The A?(1-38) peptide is a negative regulator of the A?(1-42) peptide implicated in Alzheimer disease progression.

ABSTRACT: The pool of ?-Amyloid (A?) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A? peptides. We examined how a naturally occurring variant, e.g. A?(1-38), interacts with the AD-related variant, A?(1-42), and the predominant physiological variant, A?(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A?(1-38) interacts differently with A?(1-40) and A?(1-42) and, in general, A?(1-38) interferes with the conversion of A?(1-42) to a ?-sheet-rich aggregate. Functionally, A?(1-38) reverses the negative impact of A?(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A?(1-42) phenotype in Caenorhabditis elegans. A?(1-38) also reverses any loss of MTT conversion induced by A?(1-40) and A?(1-42) in HT-22 hippocampal neurons and APOE ?4-positive human fibroblasts, although the combination of A?(1-38) and A?(1-42) inhibits MTT conversion in APOE ?4-negative fibroblasts. A greater ratio of soluble A?(1-42)/A?(1-38) [and A?(1-42)/A?(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A?(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A?(1-42).

SUBMITTER: Quartey MO

PROVIDER: S-EPMC7801637 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The Aβ(1-38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression.

Quartey Maa O MO Nyarko Jennifer N K JNK Maley Jason M JM Barnes Jocelyn R JR Bolanos Maria A C MAC Heistad Ryan M RM Knudsen Kaeli J KJ Pennington Paul R PR Buttigieg Josef J De Carvalho Carlos E CE Leary Scot C SC Parsons Matthew P MP Mousseau Darrell D DD

Scientific reports 20210111 1

The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1-38), interacts with the AD-related variant, Aβ(1-42), and the predominant physiological variant, Aβ(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1-38) interacts differently with Aβ ...[more]

PMID: 33432101

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Project description:ObjectiveThe diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF A?42/A?40 and A?42/A?38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF A?42 alone.MethodsThe study comprised three different cohorts (n = 1182) in whom CSF levels of A?42, A?40, and A?38 were assessed. CSF A?s were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid ((18)F-flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well-characterized patients.ResultsWhen using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF A?42/A?40 and A?42/A?38 ratios were significantly better predictors of abnormal amyloid PET than CSF A?42. Lower A?42, A?42/A?40, and A?42/A?38 ratios, but not A?40 and A?38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower A?38, A?40, and A?42, but not the ratios, correlated with non-AD-specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the A?42/A?40 and A?42/A?38 ratios showed increased accuracy compared to A?42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all A?s (including A?42) were decreased.InterpretationThe CSF A?42/A?40 and A?42/A?38 ratios are significantly better than CSF A?42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non-AD dementias. The ratios reflect AD-type pathology better, whereas decline in CSF A?42 is also associated with non-AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF A?42 should be used in the clinical work-up of AD.

Dataset Information

The A?(1-38) peptide is a negative regulator of the A?(1-42) peptide implicated in Alzheimer disease progression.

Publications

The Aβ(1-38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression.

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