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

ABSTRACT: 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(1-40) and Aβ(1-42) and, in general, Aβ(1-38) interferes with the conversion of Aβ(1-42) to a β-sheet-rich aggregate. Functionally, Aβ(1-38) reverses the negative impact of Aβ(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1-42) phenotype in Caenorhabditis elegans. Aβ(1-38) also reverses any loss of MTT conversion induced by Aβ(1-40) and Aβ(1-42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1-38) and Aβ(1-42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1-42)/Aβ(1-38) [and Aβ(1-42)/Aβ(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 Aβ(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(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:IntroductionThe beneficial effects of amyloid beta 1-38, or Aβ(1-38), on Alzheimer's disease (AD) progression in humans in vivo remain controversial. We investigated AD patients' cerebrospinal fluid (CSF) Aβ(1-38) and AD progression.MethodsCognitive function and diagnostic change were assessed annually for 3 years in 177 Aβ-positive participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia from the German Center for Neurodegenerative Diseases (DZNE) longitudinal cognitive impairment and dementia study (DELCODE) cohort using the Mini-Mental State Examination (MMSE), Preclinical Alzheimer's Cognitive Composite (PACC), Clinical Dementia Rating (CDR), and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Mixed linear and Cox regression analyses were conducted. CSF was collected at baseline.ResultsHigher Aβ(1-38) levels were associated with slower PACC (p = 0.001) and slower CDR Sum of Boxes (CDR-SB) (p = 0.002) but not MMSE decline. Including Aβ(1-40) beyond Aβ(1-38) in the model confirmed an association of Aβ(1-38) with slower PACC decline (p = 0.005), but not with CDR-SB or MMSE decline. In addition, higher Aβ(1-38) baseline levels were associated with a reduced dementia conversion risk.DiscussionFurther research is needed to understand the role of Aβ(1-38) in AD and its potential for future therapeutic strategies.HighlightsThis study not only replicates but also extends the existing findings on the role of Aβ(1-38) (amyloid beta 1-38) in Alzheimer's disease (AD) in humans in vivo. Higher baseline Aβ(1-38) levels were associated with a decreased risk of conversion to AD dementia in subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Different linear-mixed regression models suggest an association between higher Aβ(1-38) baseline levels and slower Preclinical Alzheimer's Cognitive Composite (PACC) and Clinical Dementia Rating Sum of Boxes (CDR-SB) decline. Including Aβ(1-40) beyond Aβ(1-38) in the model confirmed a link between Aβ(1-38) and PACC decline, but showed no association of Aβ(1-38) on CDR-SB and Mini-Mental State Examination (MMSE) decline. The impact of short Aβ isoforms in AD progression might have been under-investigated These findings underscore the urgent need for additional research on the role of these shorter Aβ peptides in AD, as they may hold key insights for future therapeutic strategies.

Project description:Human mini-brains (MB) are cerebral organoids that recapitulate in part the complexity of the human brain in a unique three-dimensional in vitro model, yielding discrete brain regions reminiscent of the cerebral cortex. Specific proteins linked to neurodegenerative disorders are physiologically expressed in MBs, such as APP-derived amyloids (Aβ), whose physiological and pathological roles and interactions with other proteins are not well established in humans. Here, we demonstrate that neuroectodermal organoids can be used to study the Aβ accumulation implicated in Alzheimer's disease (AD). To enhance the process of protein secretion and accumulation, we adopted a chemical strategy of induction to modulate post-translational pathways of APP using an Amyloid-β Forty-Two Inducer named Aftin-5. Secreted, soluble Aβ fragment concentrations were analyzed in MB-conditioned media. An increase in the Aβ42 fragment secretion was observed as was an increased Aβ42/Aβ40 ratio after drug treatment, which is consistent with the pathological-like phenotypes described in vivo in transgenic animal models and in vitro in induced pluripotent stem cell-derived neural cultures obtained from AD patients. Notably in this context we observe time-dependent Aβ accumulation, which differs from protein accumulation occurring after treatment. We show that mini-brains obtained from a non-AD control cell line are responsive to chemical compound induction, producing a shift of physiological Aβ concentrations, suggesting that this model can be used to identify environmental agents that may initiate the cascade of events ultimately leading to sporadic AD. Increases in both Aβ oligomers and their target, the cellular prion protein (PrPC), support the possibility of using MBs to further understand the pathophysiological role that underlies their interaction in a human model. Finally, the potential application of MBs for modeling age-associated phenotypes and the study of neurological disorders is confirmed.

Dataset Information

The Aβ(1-38) peptide is a negative regulator of the Aβ(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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