Journal Article

SOBA

Galasko, Douglas, Keene, C. Dirk, Peskind, Elaine, Daggett, Valerie, Li, Ge, Smith, Alec, Ko, Andrew, Colasurdo, Elizabeth, Paschall, Courtnie, Shea, Dylan, Jayadev, Suman

2022

Overview

The formation of toxic Amyloid β-peptide (Aβ) oligomers is one of the earliest events in the molecular pathology of Alzheimer’s Disease (AD). These oligomers lead to a variety of downstream effects, including impaired neuronal signaling, neuroinflammation, tau phosphorylation, and neurodegeneration, and it is estimated that these events begin 10 to 20 y before the presentation of symptoms. Toxic Aβ oligomers contain a nonstandard protein structure, termed α-sheet, and designed α–sheet peptides target this main-chain structure in toxic oligomers independent of sequence. Here we show that a designed α–sheet peptide inhibits the deleterious effects on neuronal signaling and also serves as a capture agent in our soluble oligomer binding assay (SOBA). Pre-incubated synthetic α–sheet-containing Aβ oligomers produce strong SOBA signals, while monomeric and β-sheet protofibrillar Aβ do not. α–sheet containing oligomers were also present in cerebrospinal fluid (CSF) from an AD patient versus a noncognitively impaired control. For the detection of toxic oligomers in plasma, we developed a plate coating to increase the density of the capture peptide. The proof of concept was achieved by testing 379 banked human plasma samples. SOBA detected Aβ oligomers in patients on the AD continuum, including controls who later progressed to mild cognitive impairment. In addition, SOBA discriminated AD from other forms of dementia, yielding sensitivity and specificity of 99% relative to clinical and neuropathological diagnoses. To explore the broader potential of SOBA, we adapted the assay for a-synuclein oligomers and confirmed their presence in CSF from patients with Parkinson’s disease and Lewy body dementia.

• Publisher: National Academy of Sciences
• Subject: Alzheimer Disease - blood / Alzheimer Disease - cerebrospinal fluid / Alzheimer Disease - metabolism / Alzheimer's disease / Amyloid beta-Peptides - blood / Amyloid beta-Peptides - cerebrospinal fluid / Amyloid beta-Peptides - metabolism / Amyloidogenesis / Assaying / Binding / Biological Sciences / Biophysics and Computational Biology / Blood plasma / Cerebrospinal fluid / Cerebrospinal Fluid - chemistry / Cognitive ability / Dementia / Dementia disorders / Downstream effects / Humans / Immunoenzyme Techniques - methods / Inflammation / Lewy bodies / Lewy Body Disease - blood / Lewy Body Disease - cerebrospinal fluid / Lewy Body Disease - metabolism / Movement disorders / Neurodegeneration / Neurodegenerative diseases / Oligomers / Parkinson Disease - blood / Parkinson Disease - cerebrospinal fluid / Parkinson Disease - metabolism / Parkinson's disease / Peptide Fragments - blood / Peptide Fragments - cerebrospinal fluid / Peptide Fragments - metabolism / Peptides / Phosphorylation / Protein structure / Signaling / Signs and symptoms / Synuclein / Tau protein / β-Amyloid