Brain site-specific proteome changes in aging-related dementia

Abstract

This study is aimed at gaining insights into the brain site-specific proteomic senescence signature while comparing physiologically aged brains with aging-related dementia brains (for example, Alzheimer's disease (AD)). Our study of proteomic differences within the hippocampus (Hp), parietal cortex (pCx) and cerebellum (Cb) could provide conceptual insights into the molecular mechanisms involved in aging-related neurodegeneration. Using an isobaric tag for relative and absolute quantitation (iTRAQ)-based two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC-MS/MS) brain site-specific proteomic strategy, we identified 950 proteins in the Hp, pCx and Cb of AD brains. Of these proteins, 31 were significantly altered. Most of the differentially regulated proteins are involved in molecular transport, nervous system development, synaptic plasticity and apoptosis. Particularly, proteins such as Gelsolin (GSN), Tenascin-R (TNR) and AHNAK could potentially act as novel biomarkers of aging-related neurodegeneration. Importantly, our Ingenuity Pathway Analysis (IPA)-based network analysis further revealed ubiquitin C (UBC) as a pivotal protein to interact with diverse AD-associated pathophysiological molecular factors and suggests the reduced ubiquitin proteasome degradation system (UPS) as one of the causative factors of AD.

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

“…This theory is further supported by previous results that indicated proteasome activity impairment in AD-related neurodegeneration [266,267,[341][342][343][344]. Furthermore, a human in vivo study that used the metabolic marker 13 C 6 -leucine to trace the production and clearance rates of Aβ 40 and Aβ 42 in the CSF indicated that Aβ was produced at the same rate in both the AD (which ranged from very mild to mild AD) and control groups; however, the Aβ clearance in the AD group was significantly (~35 %) lower than the control group.…”

“…In addition, other pivotal proteins of the chaperone/ proteasomal pathways, such as heat shock proteins (HSPs), FK506-binding proteins (FKBPs), and tripartite motif (TRIM) family proteins, were also altered in AD [118,267].…”

Proteomics of the Synapse – A Quantitative Approach to Neuronal Plasticity

“…With the advent of quantitative proteomics using ICAT (65), iTRAQ (66), AQUA (67), SILAC (68), SILAM (69), and label-free quantification approaches (70) some of these issues have been resolved and differential proteomic profiling in combination with absolute and relative quantifications can address changes of the neuronal proteome associated with diseases (e.g. [71][72][73][74][75][76][77][78][79] or is able to tackle protein half-lives (80,81). Crucial to all of these approaches are absolute high fidelity in the technical prerequisites of the analyses including accuracy of workflows, validity of data, dynamic range of protein assessment, or PTM levels.…”

XPR1: a Gene Linked to Primary Familial Brain Calcification Might Help Explain a Spectrum of Neuropsychiatric Disorders

“…Among their findings is a FUS-regulated alternative splicing of XPR1, which causes the elongation of Exon 13 on motor and cortical neurons. Manavalan et al (2013) analyzed proteome changes in brain linked to aging-related dementia. XPR1 molecule was included in the hippocampus network along with other 34 proteins whose expression is modulated in the hippocampus in AD brains.…”