First evidence of overlaps between HIV-Associated Dementia (HAD) and non-viral neurodegenerative diseases: proteomic analysis of the frontal cortex from HIV+ patients with and without dementia

Li Zhou,Rejane Rua,Nitin K Saksena,Kaushal Gandhi,Sieu L Tran,Thomas Ng,Helen Rizos,Bruce J Brew,Ben Crossett,Eve Diefenbach,Bin Wang,Amit Kapur

doi:10.1186/1750-1326-5-27

Abstract

BackgroundThe pathogenesis of HIV-associated dementia (HAD) is poorly understood. To date, detailed proteomic fingerprinting directly from autopsied brain tissues of HAD and HIV non-dementia patients has not been performed.ResultHere, we have analyzed total proteins from the frontal cortex of 9 HAD and 5 HIV non-dementia patients. Using 2-Dimensional differential in-gel electrophoresis (2-DIGE) to analyze the brain tissue proteome, 76 differentially expressed proteins (p < 0.05; fold change>1.25) were identified between HAD and HIV non-dementia patients, of which 36 protein spots (based on 3D appearance of spots on the images) were chosen for the mass spectrometry analysis. The large majority of identified proteins were represented in the energy metabolic (mitochondria) and signal transduction pathways. Furthermore, over 90% of the protein candidates are common to both HAD and other non-viral neurodegenerative disease, such as Alzheimer's disease. The data was further validated using specific antibodies to 4 proteins (CA2, GS, CKMT and CRMP2) by western blot (WB) in the same samples used for 2D-DIGE, with additional confirmation by immunohistochemitsry (IHC) using frontal lobe tissue from different HAD and HIV+ non-dementia patients. The validation for all 4 antibodies by WB and IHC was in concordance with the DIGE results, lending further credence to the current findings.ConclusionThese results suggest not only convergent pathogenetic pathways for the two diseases but also the possibility of increased Alzheimer's disease (AD) susceptibility in HAD patients whose life expectancy has been significantly increased by highly active antiretroviral therapy.

Highlights

The pathogenesis of HIV-associated dementia (HAD) is poorly understood
These results suggest convergent pathogenetic pathways for the two diseases and the possibility of increased Alzheimer's disease (AD) susceptibility in HAD patients whose life expectancy has been significantly increased by highly active antiretroviral therapy
A total of 958 protein spots were detected on the master gel (893.14 ± 96.07 spots across all the individual gels), 76 of which were found to change significantly in HAD brains compared to HIV non-demented brains according to the criteria that a spot had to be present in at least 16 of the 21 images; the fold change had to be at least 1.25 with a P value less than 0.05

Summary

Introduction

The pathogenesis of HIV-associated dementia (HAD) is poorly understood. To date, detailed proteomic fingerprinting directly from autopsied brain tissues of HAD and HIV non-dementia patients has not been performed. HIV-1 associated dementia (HAD) is a common complication of HIV disease with a prevalence of at least 20% in advanced HIV infection in the pre-highly active antiretroviral therapy (HAART) era [1]. Even in patients taking HAART, milder forms of cognitive impairment remain common and functionally significant [2]. The reasons for the continued presence and development of HAD and its milder forms, despite effective HAART are not clear. Due to the longevity of HIV patients after the advent of HAART, the prevalence of HAD has increased [3]. It has been hypothesized that Alzheimer's disease will significantly increase among elderly HIV-infected individuals [4]. There is the possibility of HIV initiating or facilitating a neurodegenerative process

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Conclusion