Molecular properties underlying regional vulnerability to Alzheimer's disease pathology.
Molecular properties underlying regional vulnerability to Alzheimer's disease pathology.
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DOI：
10.1093/brain/awy189
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发表时间：
2018-09-01
期刊：
影响因子：
--
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
中科院分区：
文献类型：
--
作者：
Grothe MJ;Sepulcre J;Gonzalez-Escamilla G;Jelistratova I;Schöll M;Hansson O;Teipel SJ;Alzheimer’s Disease Neuroimaging Initiative
See Lowe et al. (doi:) for a scientific commentary on this article. Alzheimer’s disease targets discrete neural systems, but the mechanisms underlying this regionally selective vulnerability remain unknown. Grothe et al. report that Alzheimer’s disease pathology specifically affects brain regions with certain molecular properties, and that the biological pathways underlying this vulnerability differ for amyloid accumulation versus neurodegeneration. Amyloid deposition and neurofibrillary degeneration in Alzheimer’s disease specifically affect discrete neuronal systems, but the underlying mechanisms that render some brain regions more vulnerable to Alzheimer’s disease pathology than others remain largely unknown. Here we studied molecular properties underlying these distinct regional vulnerabilities by analysing Alzheimer’s disease-typical neuroimaging patterns of amyloid deposition and neurodegeneration in relation to regional gene expression profiles of the human brain. Graded patterns of brain-wide vulnerability to amyloid deposition and neurodegeneration in Alzheimer’s disease were estimated by contrasting multimodal amyloid-sensitive PET and structural MRI data between patients with Alzheimer’s disease dementia (n = 76) and healthy controls (n = 126) enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen brain atlas of the adult human brain transcriptome. In a hypothesis-driven analysis focusing on the genes coding for the amyloid precursor (APP) and tau proteins (MAPT), regional expression levels of APP were positively correlated with the severity of regional amyloid deposition (r = 0.44, P = 0.009), but not neurodegeneration (r = 0.01, P = 0.96), whereas the opposite pattern was observed for MAPT (neurodegeneration: r = 0.46, P = 0.006; amyloid: r = 0.08, P = 0.65). Using explorative gene set enrichment analysis, amyloid-vulnerable regions were found to be characterized by relatively low expression levels of gene sets implicated in protein synthesis and mitochondrial respiration. By contrast, neurodegeneration-vulnerable regions were characterized by relatively high expression levels of gene sets broadly implicated in neural plasticity, with biological functions ranging from neurite outgrowth and synaptic contact over intracellular signalling cascades to proteoglycan metabolism. At the individual gene level this data-driven analysis further corroborated the association between neurodegeneration and MAPT expression, and additionally identified associations with known tau kinases (CDK5, MAPK1/ERK2) alongside components of their intracellular (Ras-ERK) activation pathways. Sensitivity analyses showed that these pathology-specific imaging-genetic associations were largely robust against changes in some of the methodological parameters, including variation in the brain donor sample used for estimating regional gene expression profiles, and local variations in the Alzheimer’s disease-typical imaging patterns when these were derived from an independent patient cohort (BioFINDER study). These findings highlight that the regionally selective vulnerability to Alzheimer’s disease pathology relates to specific molecular-functional properties of the affected neural systems, and that the implicated biochemical pathways largely differ for amyloid accumulation versus neurodegeneration. The data provide novel insights into the complex pathophysiological mechanisms of Alzheimer’s disease and point to pathology-specific treatment targets that warrant further exploration in independent studies.
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影响因子：
4.2
作者：
Biffi A;Sabuncu MR;Desikan RS;Schmansky N;Salat DH;Rosand J;Anderson CD;Alzheimer's disease Neuroimaging Initiative (ADNI)
通讯作者：
Alzheimer's disease Neuroimaging Initiative (ADNI)
影响因子：
4.3
作者：
Hansson O;Grothe MJ;Strandberg TO;Ohlsson T;Hägerström D;Jögi J;Smith R;Schöll M
通讯作者：
Schöll M
影响因子：
4.8
作者：
Grothe MJ;Teipel SJ;Alzheimer's Disease Neuroimaging Initiative
通讯作者：
Alzheimer's Disease Neuroimaging Initiative
影响因子：
3.7
作者：
Fjell, Anders M.;Amlien, Inge K.;Walhovd, Kristine B.
通讯作者：
Walhovd, Kristine B.
影响因子：
11.2
作者：
Cho, Hanna;Choi, Jae Yong;Lyoo, Chul Hyoung
通讯作者：
Lyoo, Chul Hyoung