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A? Beyond the AD Pathology: Exploring the Structural Response of Membranes Exposed to Nascent A? Peptide.

ABSTRACT: The physiological and pathological roles of nascent amyloid beta (A?) monomers are still debated in the literature. Their involvement in the pathological route of Alzheimer's Disease (AD) is currently considered to be the most relevant, triggered by their aggregation into structured oligomers, a toxic species. Recently, it has been suggested that nascent A?, out of the amyloidogenic pathway, plays a physiological and protective role, especially in the brain. In this emerging perspective, the study presented in this paper investigated whether the organization of model membranes is affected by contact with A? in the nascent state, as monomers. The outcome is that, notably, the rules of engagement and the resulting structural outcome are dictated by the composition and properties of the membrane, rather than by the A? variant. Interestingly, A? monomers are observed to favor the tightening of adjacent complex membranes, thereby affecting a basic structural event for cell-cell adhesion and cell motility.

SUBMITTER: Rondelli V

PROVIDER: S-EPMC7663943 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Aβ Beyond the AD Pathology: Exploring the Structural Response of Membranes Exposed to Nascent Aβ Peptide.

Rondelli Valeria V Salmona Mario M Colombo Laura L Fragneto Giovanna G Fadda Giulia C GC Cantu' Laura L Del Favero Elena E

International journal of molecular sciences 20201105 21

The physiological and pathological roles of nascent amyloid beta (Aβ) monomers are still debated in the literature. Their involvement in the pathological route of Alzheimer's Disease (AD) is currently considered to be the most relevant, triggered by their aggregation into structured oligomers, a toxic species. Recently, it has been suggested that nascent Aβ, out of the amyloidogenic pathway, plays a physiological and protective role, especially in the brain. In this emerging perspective, the stu ...[more]

PMID: 33167440

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Project description:Currently, there are very limited pharmaceutical interventions for Alzheimer's disease (AD) to alleviate the amyloid burden implicated in the pathophysiology of the disease. Alzheimer's disease is characterized immunohistologically by the accumulation of senile plaques in the brain with afflicted patients progressively losing short-term memory and, ultimately, cognition. Although significant improvements in clinical diagnosis and care for AD patients have been made, effective treatments for this devastating disease remain elusive. A key component of the amyloid burden of AD comes from accumulation of the amyloid-beta (Aβ) peptide which comes from processing of the amyloid precursor protein (APP) by enzymes termed secretases, leading to production of these toxic Aβ peptides of 40-42 amino acids. New therapeutic approaches for reducing Aβ are warranted after the most logical avenues of inhibiting secretase activity appear less than optimal in ameliorating the progression of AD.Novel therapeutics may be gleaned from proteomics biomarker initiatives to yield detailed molecular interactions of enzymes and their potential substrates. Explicating the APPome by deciphering protein complexes forming in cells is a complementary approach to unveil novel molecular interactions with the amyloidogenic peptide precursor to both understand the biology and develop potential upstream drug targets. Utilizing these strategies we have identified EC 3.4.24.15 (EP24.15), a zinc metalloprotease related to neprilysin (NEP), with the ability to catabolize Aβ 1-42 by examining first potential in silico docking and then verification by mass spectrometry. In addition, a hormone carrier protein, transthyreitin (TTR), was identified and with its abundance in cerebrospinal fluid (CSF), found to clear Aβ by inhibiting formation of oligomeric forms of Aβ peptide. The confluence of complementary strategies may allow new therapeutic avenues as well as biomarkers for AD that will aid in diagnosis, prognosis and treatment.

Dataset Information

A? Beyond the AD Pathology: Exploring the Structural Response of Membranes Exposed to Nascent A? Peptide.

Publications

Aβ Beyond the AD Pathology: Exploring the Structural Response of Membranes Exposed to Nascent Aβ Peptide.

Similar Datasets

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