Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau

Abstract

The repeated failures of amyloid-targeting therapies have challenged our narrow understanding of Alzheimer’s disease (AD) pathogenesis and inspired wide-ranging investigations into the underlying mechanisms of disease. Increasing evidence indicates that AD develops from an intricate web of biochemical and cellular processes that extend far beyond amyloid and tau accumulation. This growing recognition surrounding the diversity of AD pathophysiology underscores the need for holistic systems-based approaches to explore AD pathogenesis. Here we describe how network-based proteomics has emerged as a powerful tool and how its application to the AD brain has provided an informative framework for the complex protein pathophysiology underlying the disease. Furthermore, we outline how the AD brain network proteome can be leveraged to advance additional scientific and translational efforts, including the discovery of novel protein biomarkers of disease.

Detection and Purification of Lewy Pathology from Formalin Fixed Primary Human Tissue Using Biotinylation by Antigen Recognition

“…In conclusion, the technique described here can be used for highly sensitive detection and enrichment of Lewy pathology from formalin fixed brain tissues. Conceptually, we have provided a framework to explore the molecular details of Lewy pathology in primary human tissues and this could instigate a systems based approach for understanding the molecular architecture of Lewy pathology 26 . The modified BAR protocol enriched for proteins within Lewy pathology and possibly adjacent to Lewy pathology (i.e.…”

Activation of M1muscarinic receptors reduce pathology and slow progression of neurodegenerative disease

“…C1qA,B,C) (Fig 2B,C). Significantly, many of these neuroinflammatory markers are also reported to be up-regulated in AD 28,29 . Furthermore, the prion-effect included an up-regulation of other proteins considered markers of AD 28,29 .…”

“…Significantly, many of these neuroinflammatory markers are also reported to be up-regulated in AD 28,29 . Furthermore, the prion-effect included an up-regulation of other proteins considered markers of AD 28,29 . This included, for example, the up-regulation of several members of the apolipoprotein family (Fig 2B, Supplementary Table S2 and S3) including ApoE.…”

Proteomics Landscape of Alzheimer’s Disease

“…Chou et al has discussed the effects of multiple post-translational modifications including phosphorylation, acetylation, SUMOylation, O-GlcNAcylation, and ubiquitination of tau on AD pathology in their review article [ 101 ]. A recent review by Rayaprolu et al describes how a network-based proteomics approach can be leveraged to improve our narrow understanding of AD biology beyond amyloid plaques and tau phosphorylation [ 102 ]. These post-translation modification-related proteomics studies on human postmortem brain specimen or animal models are useful for the understanding of the altered signaling networks in AD pathogenesis.…”