APP/Aβ structural diversity and Alzheimer's disease pathogenesis

Abstract

The amyloid cascade hypothesis of Alzheimer’s disease (AD) proposes amyloid-β (Aβ) is a chief pathological element of dementia. AD therapies have targeted monomeric and oligomeric Aβ 1-40 and 1-42 peptides. However, alternative APP proteolytic processing produces a complex roster of Aβ species. In addition, Aβ peptides are subject to extensive posttranslational modification (PTM). We propose that amplified production of some APP/Aβ species, perhaps exacerbated by differential gene expression and reduced peptide degradation, creates a diverse spectrum of modified species which disrupt brain homeostasis and accelerate AD neurodegeneration. We surveyed the literature to catalog Aβ PTM including species with isoAsp at positions 7 and 23 which may phenocopy the Tottori and Iowa Aβ mutations that result in early onset AD. We speculate that accumulation of these alterations induce changes in secondary and tertiary structure of Aβ that favor increased toxicity, and seeding and propagation in sporadic AD. Additionally, amyloid-β peptides with a pyroglutamate modification at position 3 and oxidation of Met35 make up a substantial portion of sporadic AD amyloid deposits. The intrinsic physical properties of these species, including resistance to degradation, an enhanced aggregation rate, increased neurotoxicity, and association with behavioral deficits, suggest their emergence is linked to dementia. The generation of specific 3D-molecular conformations of Aβ impart unique biophysical properties and a capacity to seed the prion-like global transmission of amyloid through the brain. The accumulation of rogue Aβ ultimately contributes to the destruction of vascular walls, neurons and glial cells culminating in dementia. A systematic examination of Aβ PTM and the analysis of the toxicity that they induced may help create essential biomarkers to more precisely stage AD pathology, design countermeasures and gauge the impacts of interventions.

Chiral Interface of Amyloid Beta (Aβ): Relevance to Protein Aging, Aggregation and Neurodegeneration

“…With the recognition of the fact that many proteins (Aβ, TAU, prion protein Prion (PrP), Huntingtin and α-synuclein) are the substrate of the aggregation-prone PTMs Sp [6], we are focusing, primarily, on the racemization of the Aβ. The amyloid precursor protein (APP) is one of the most studied proteins concerning pathological misfolding.…”

Proteases: Pivot Points in Functional Proteomics

“…However, no clear correlation could be made between plasma Aβ fragment concentrations and AD, dementia and various stages of cognitive decline, perhaps in part due to the limited sensitivity of the current analytical methods [156]. Due to observed discrepancies between AD dementia and amyloid deposition, some groups have suggested that either soluble oligomeric Aβ peptides may be more toxic, or that tau neurofibrillary tangles may be the pathogenic species [157]. …”

Sex Hormones and Alzheimer’s Disease

“…Amyloid plaques are aggregates of amyloid beta (Aβ) peptide derived mainly from the cleavage of a transmembrane protein named amyloid precursor protein (APP) by the sequential action of two aspartyl protease enzymes, β-and γ-secretases (amyloidogenic pathway) in which the APP is firstly cleaved by β-secretase to soluble APP and residual C-terminal segment that is further digested by the γ-secretase to Aβ-40/42 segments. The insoluble Aβ aggregates start to appear 15-25 years prior to the onset of cognitive decline or tau pathology, and their formation is triggered by enhancement of the amyloidogenic pathway with increasing the pool of soluble Aβ production, which in turn aggregate to form monomeric, oligomeric, protofibrils and finally mature insoluble Aβ [10]. Under normal circumstances, the ratio of Aβ-42: Aβ-40 is 1:9 and increase in this ratio due to either aberrant production (increased γ-secretase activity) or clearance (abnormal microglial activities) is the cause of Aβ accumulation as the former has a high tendency to aggregate.…”

“…Many studies revealed that people with a rare missense mutation (rs75932628-T) in the gene encoding TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) are at increased risk of developing AD 2-3 folds than others possibly due to reduced clearing abilities of their microglia to Aβ and apoptotic cells [10]. At the same time, other studies suggested a possible role of epigenetic changes and aberrantly expressed micro-RNAs (miRNAs) in the pathogenesis of AD through disturbing neurogenesis, synaptic plasticity, synaptogenesis and neuronal network preservation as well as enhancing Aβ production and neuroinflammation [27].…”