Choroid Plexus Acts as Gatekeeper for TREM2, Abnormal Accumulation of ApoE, and Fibrillary Tau in Alzheimer's Disease and in Down Syndrome Dementia.

Autor:	Raha-Chowdhury R; Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, Cambridge, UK.; John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK., Henderson JW; John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK., Raha AA; John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK., Vuono R; John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK., Bickerton A; Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, Cambridge, UK., Jones E; Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, Cambridge, UK., Fincham R; Clinical Pathology, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Allinson K; Clinical Pathology, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Holland A; Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, Cambridge, UK., Zaman SH; Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, Cambridge, UK.; Cambridgeshire and Peterborough Foundation NHS Trust, Cambridge, UK.
Jazyk:	angličtina
Zdroj:	Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2019; Vol. 69 (1), pp. 91-109.
DOI:	10.3233/JAD-181179
Abstrakt:	Background: Genetic factors that influence Alzheimer's disease (AD) risk include mutations in TREM2 and allelic variants of Apolipoprotein E, influencing AD pathology in the general population and in Down syndrome (DS). Evidence shows that dysfunction of the choroid plexus may compromise the blood-cerebrospinal fluid (CSF) barrier, altering secretary, transport and immune function that can affect AD pathology. Objective: To investigate the genotype and phenotype of DS individuals in relation to choroid plexus damage and blood-CSF barrier leakage to identify markers that could facilitate early diagnosis of AD in DS. Methods: To assess allele frequency and haplotype associations ApoE, Tau, TREM2, and HLA-DR were analyzed by SNP analysis in DS participants (n = 47) and controls (n = 50). The corresponding plasma protein levels were measured by ELISA. Postmortem brains from DS, AD, and age-matched controls were analyzed by immunohistochemistry. Results: Haplotype analysis showed that individuals with Tau H1/H1 and ApoEɛ4 genotypes were more prevalent among DS participants with an earlier diagnosis of dementia (17%) compared to H1/H2 haplotypes (6%). Plasma TREM2 levels decreased whereas phospho-tau levels increased with age in DS. In AD and DS brain, insoluble tau and ApoE were found to accumulate in the choroid plexus. Conclusion: Accumulation of tau and ApoE in the choroid plexus may increase the oligomerization rate of Aβ42 and impair tau trafficking, leading to AD pathology. We have identified a high-risk haplotype: ApoEɛ4, Tau/H1, and TREM2/T, that manifests age-related changes potentially opening a window for treatment many years prior to the manifestation of the AD dementia.
Databáze:	MEDLINE
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