title: Mitochondrial dysfunction and immune activation are detectable in early Alzheimer's disease blood.
abstract: Alzheimer's disease (AD), like other dementias, is characterized by progressive neuronal loss and neuroinflammation in the brain. The peripheral leukocyte response occurring alongside these brain changes has not been extensively studied, but might inform therapeutic approaches and provide relevant disease biomarkers. Using microarrays, we assessed blood gene expression alterations occurring in people with AD and those with mild cognitive changes at increased risk of developing AD. Of the 2,908 differentially expressed probes identified between the three groups (p < 0.01), a quarter were altered in blood from mild cognitive impairment (MCI) and AD subjects, relative to controls, suggesting a peripheral response to pathology may occur very early. There was strong evidence for mitochondrial dysfunction with decreased expression of many of the respiratory complex I-V genes and subunits of the core mitochondrial ribosome complex. This mirrors changes previously observed in AD brain. A number of genes encoding cell adhesion molecules were increased, along with other immune-related genes. These changes are consistent with leukocyte activation and their increased the transition from circulation into the brain. In addition to expression changes, we also found increased numbers of basophils in people with MCI and AD, and increased monocytes in people with an AD diagnosis. Taken together this study provides both an insight into the functional response of circulating leukocytes during neurodegeneration and also identifies potential targets such as the respiratory chain for designing and monitoring future therapeutic interventions using blood.
authors.affiliation: Institute of Psychiatry, King's Health Partners Centre for Neurodegeneration Research, King's College London, London, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Lunnon
authors.forename: Zina
authors.initials: Z
authors.lastname: Ibrahim
authors.forename: Petroula
authors.initials: P
authors.lastname: Proitsi
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Lourdusamy
authors.forename: Stephen
authors.initials: S
authors.lastname: Newhouse
authors.forename: Martina
authors.initials: M
authors.lastname: Sattlecker
authors.forename: Simon
authors.initials: S
authors.lastname: Furney
authors.forename: Muzamil
authors.initials: M
authors.lastname: Saleem
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Iwona
authors.initials: I
authors.lastname: Kłoszewska
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mecocci
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Daniel
authors.initials: D
authors.lastname: Geschwind
authors.forename: Andrew
authors.initials: A
authors.lastname: Simmons
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Richard
authors.initials: R
authors.lastname: Dobson
authors.forename: Angela
authors.initials: A
authors.lastname: Hodges
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D001491:Basophils / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000097:blood* / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D009000:Monocytes / Q000378:metabolism; D009483:Neuropsychological Tests
chemical_list: D045222:Electron Transport Chain Complex Proteins