Development of molecular tools for diagnosis of Alzheimer’s disease that are based on detection of amyloidogenic proteins

Abstract

Alzheimer’s disease (AD) is the most common form of dementia that usually occurs among older people. AD results from neuronal degeneration that leads to the cognitive impairment and death. AD is incurable, typically develops over the course of many years and is accompanied by a loss of functional autonomy, making a patient completely dependent on family members and/or healthcare workers. Critical features of AD are pathological polymerization of Aβ peptide and microtubule-associated protein tau, accompanied by alterations of their conformations and resulting in accumulation of cross-β fibrils (amyloids) in human brains. AD apparently progresses asymptomatically for years or even decades before the appearance of symptoms. Therefore, development of the early AD diagnosis at a pre-symptomatic stage is essential for potential therapies. This review is focused on current and potential molecular tools (including non-invasive methods) that are based on detection of amyloidogenic proteins and can be applicable to early diagnosis of AD. Abbreviations : Aβ – amyloid-β peptide; AβO – amyloid-β oligomers; AD – Alzheimer’s disease; ADRDA – Alzheimer’s Disease and Related Disorders Association; APH1 - anterior pharynx defective 1; APP – amyloid precursor protein; BACE1 – β-site APP-cleaving enzyme 1; BBB – brain blood barrier; CJD - Creutzfeldt-Jakob disease; CRM – certified reference material; CSF – cerebrospinal fluid; ELISA – enzyme-linked immunosorbent assay; FGD – 18 F-fluorodesoxyglucose (2-deoxy-2-[ 18 F]fluoro-D-glucose); IP-MS – immunoprecipitation-mass spectrometry assay; MCI – mild cognitive impairment; MDS – multimer detection system; MRI – magnetic resonance imaging; NIA-AA – National Institute on Ageing and Alzheimer’s Association; NINCDS – National Institute of Neurological and Communicative Disorders and Stroke; PEN2 – presenilin enhancer 2; PET – positron emission tomography; PiB – Pittsburgh Compound B; PiB-SUVR - PIB standardized uptake value ratio; PMCA – Protein Misfolding Cycling Amplification; PrP – Prion Protein; P-tau – hyperphosphorylated tau protein; RMP – reference measurement procedure; RT-QuIC - real-time quaking-induced conversion; SiMoA – single-molecule array; ThT – thioflavin T; TSEs – Transmissible Spongiform Encephslopathies; T-tau – total tau protein

Plasma tau proteins for the diagnosis of mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis

“…One reason is that tau levels in the circulation are much lower than those in the CSF. Blood-brain barrier (BBB) acts as a selective filter, so that these brain proteins may be cleaved, modified or degraded before or after passing BBB (Kulichikhin et al, 2021 ). Biomarker levels in peripheral blood tend to be near the lower limits of detection of current ELISA assays and close to the low-end of the linear range of a calibration curve.…”

Cyclic-NDGA Effectively Inhibits Human γ-Synuclein Fibrillation, Forms Nontoxic Off-Pathway Species, and Disintegrates Preformed Mature Fibrils

“…Fibril formation was monitored using thioflavin T (ThT) dye, which results in enhanced fluorescence upon binding to amyloid structures. , The ThT stock solution was prepared in fibrillation buffer (20 mM sodium phosphate buffer and 100 mM sodium chloride, pH 7.4) and its concentration was measured at 412 nm using molar extinction coefficient of 35,000 M –1 cm –1 . cNDGA stock was prepared in 100% DMSO and its concentration was measured at 288 nm.…”

Is liquid biopsy mature enough for the diagnosis of Alzheimer’s disease?

“…To solve this problem, several ultra-high-sensitivity technologies capable of quantifying concentrations of biomarkers not only in CSF but also in blood have been developed. These innovative technologies can be applied to the early stage diagnosis of AD (Kulichikhin et al, 2021).…”