Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in the human population, characterized by a spectrum of neuropathological abnormalities that results in memory impairment and loss of other cognitive processes as well as the presence of non-cognitive symptoms. Transcriptomic analyses provide an important approach to elucidating the pathogenesis of complex diseases like AD, helping to figure out both pre-clinical markers to identify susceptible patients and the early pathogenic mechanisms to serve as therapeutic targets. This study provides the gene expression profile of postmortem brain tissue from subjects with clinic-pathological AD (Braak IV, V, or V and CERAD B or C; and CDR ≥1), preclinical AD (Braak IV, V, or VI and CERAD B or C; and CDR = 0), and healthy older individuals (Braak ≤ II and CERAD 0 or A; and CDR = 0) in order to establish genes related to both AD neuropathology and clinical emergence of dementia. Based on differential gene expression, hierarchical clustering and network analysis, genes involved in energy metabolism, oxidative stress, DNA damage/repair, senescence, and transcriptional regulation were implicated with the neuropathology of AD; a transcriptional profile related to clinical manifestation of AD could not be detected with reliability using differential gene expression analysis, although genes involved in synaptic plasticity, and cell cycle seems to have a role revealed by gene classifier. In conclusion, the present data suggest gene expression profile changes secondary to the development of AD-related pathology and some genes that appear to be related to the clinical manifestation of dementia in subjects with significant AD pathology, making necessary further investigations to better understand these transcriptional findings on the pathogenesis and clinical emergence of AD.

Highlights

  • Alzheimer’s disease (AD) is the most frequent dementing disorder in the elderly and is characterized by a progressive decline in memory and other cognitive domains [1]

  • Gene Expression Profile Related to AD Pathology To address which genes were related to the neuropathological processes of AD (‘‘neuropathological AD-related genes’’, npADGs), we compared the gene expression profile (Student’s ttest, P#0.01) of subjects who have been histopathologically confirmed to demonstrate pathologies associated with AD (Braak stage $ IV and CERAD = B or C, n = 13; representing the CPAD and preclinical Alzheimer’s disease (P-AD) groups) and subjects without evidence of ADrelated pathology (Braak stage # II and CERAD = 0 or A, n = 10; representing the N group)

  • We included a group of subjects with preclinical AD - a period during which there are abundant amyloid deposits and neurofibrillary tangles in the brain but no evidence of cognitive decline - to provide further support to the relevance of genes involved in the early development of neurodegenerative changes in AD

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Summary

Introduction

Alzheimer’s disease (AD) is the most frequent dementing disorder in the elderly and is characterized by a progressive decline in memory and other cognitive domains [1]. The hallmark neuropathological lesions in AD are the presence of neuritic plaques and neurofibrillary tangles, which are secondary to the deposition of b-amyloid peptide (Ab) and hyperphosphorylated tau protein [2,3] The presence of these two lesions is necessary to definite diagnosis of AD in post-mortem studies [4,5]. The most accepted pathogenic process in AD derives from the ‘‘amyloid cascades hypothesis’’. It states that accumulation of amyloid-b species in the brain, either by increased production or by reduced protein clearance, leads to several secondary pathological changes in neurons and glial cells culminating in widespread neurodegeneration (dystrophic neurites and intracellular neurofibrillary tangles) and cell death [6,7]

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