Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues.
Microarray technology was utilized to isolate disease-specific changes in gene expression by sampling across inferior parietal lobes of patients suffering from late onset AD or non-AD-associated dementia and non-demented controls. Primary focus was placed on understanding how inflammation plays a role in AD pathogenesis. Gene ontology analysis revealed that the most differentially expressed genes related to nervous system development and function and neurological disease followed by genes involved in inflammation and immunological signaling. Pathway analysis also implicated a role for chemokines and their receptors, specifically CXCR4 and CCR3, in AD. Immunohistological analysis revealed that these chemokine receptors are upregulated in AD patients. Western analysis demonstrated an increased activation of PKC, a downstream mediator of chemokine receptor signaling, in the majority of AD patients. A very specific cohort of genes related to amyloid beta accumulation and clearance were found to be significantly altered in AD. The most significantly downregulated gene in this data set was the endothelin converting enzyme 2 (ECE2), implicated in amyloid beta clearance. These data were subsequently confirmed by real-time PCR and Western blot analysis. Together, these findings open up new avenues of investigation and possible therapeutic strategies targeting inflammation and amyloid clearance in AD patients.
Weeraratna
Ashani T
AT
Laboratory of Immunology, National Institutes of Health, Baltimore, MD 21224, USA.
Kalehua
Audrey
A
Deleon
Isoke
I
Bertak
Dorothy
D
Maher
Gregory
G
Wade
Michael S
MS
Lustig
Ana
A
Becker
Kevin G
KG
Wood
William
W
Walker
Douglas G
DG
Beach
Thomas G
TG
Taub
Dennis D
DD
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D016022:Case-Control Studies; D002525:Cerebellar Cortex / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics*; D016000:Cluster Analysis; D003704:Dementia / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011493:Protein Kinase C / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation
D018925:Chemokines; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D011493:Protein Kinase C; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606924:ECE2 protein, human; D000072396:Endothelin-Converting Enzymes