Transcriptional Alterations Related to Neuropathology and Clinical Manifestation of Alzheimer's Disease

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.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2005/04151-7]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP

Interaction networks of the significant genes and their interacting partners.

<p>(<b>A</b>) Shown are the genes (color nodes) that have, as a function of presence (CP-AD + P-AD) or absence (N) of AD pathology, significantly different correlation of co-expression with their partners. Green nodes indicate genes that are significantly differently expressed between patient groups, while light blue nodes indicate genes that are not significantly differently expressed. Edge colors represent the correlation between a gene and each of its partners. (<b>B</b>) <i>MYC</i> and its interacting partners. Note that the significant genes and their partners form an interconnected network, and despite the interactions involving <i>MYC</i> are not significantly altered, it has a lot of connections, playing an important role as a hub gene. CP-AD, clinic-pathological Alzheimer’s disease; P-AD, pathological/preclinical Alzheimer’s disease; N, normal samples (controls).</p

Hierarchical clustering analysis of CP-AD, P-AD and N samples.

<p>Hierarchical clustering was performed by using the expression values from the genes related to AD neuropathology with <i>P</i>≤0.005 (47 transcripts). Each row represents a single gene and each column a sample (dark blue, CP-AD samples; light blue, P-AD samples; yellow, N samples). Red indicates upregulation, green indicates downregulation, and black indicates no change in expression level comparing to reference sample. Cluster support was given by Bootstrap technic (black, 100% of support; grey, 90–100%; blue, 80–90%; green, 70–80%; light yellow, 60–70%; dark yellow, 50–60%; magenta, 0–50%, red, 0%). CP-AD, clinic-pathological Alzheimer’s disease; P-AD, pathological/preclinical Alzheimer’s disease; N, normal samples (controls).</p

Multivariate (three-gene) discriminators for Alzheimer’s disease (AD) classification.

<p>(<b>A</b>) Discriminator of CP-AD samples (blue) and P-AD samples (red) using the expression values of <i>PTPRN</i>, <i>ULK2</i>, and <i>HES1</i> genes. (<b>B</b>) Discriminator of CP-AD samples (blue) and P-AD samples (red) using the expression values of <i>CAPRIN1</i>, <i>ULK2</i>, and <i>RFC2</i> genes. CP-AD, clinic-pathological Alzheimer’s disease; P-AD, pathological/preclinical Alzheimer’s disease.</p

Hypothetical model of the gene expression alterations related to neuropathology and clinical manifestation of Alzheimer’s disease (AD).

<p>Gene expression profile changes related to AD pathology are implicated with energy metabolism, oxidative stress, DNA damage and transcriptional regulation. Once established of significant AD pathology, some genes involved with synaptic plasticity, and cell cycle appear to be involved with the clinical outcome of the illness and might represent the molecular mechanisms that underlie the cognitive reserve. CP-AD, clinic-pathological Alzheimer’s disease; P-AD, pathological/preclinical Alzheimer’s disease.</p