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P1‐127: Assessing Trem2 Risk Variants in Alzheimer's Disease with RNA‐SEQ
Author(s) -
Carbajosa Guillermo,
Wang Hong,
Ryder John,
Collier David A.,
O'Neill Michael J.,
Dobson Richard JB.,
Newhouse Stephen J.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.875
Subject(s) - trem2 , neurodegeneration , biology , disease , gene , microarray analysis techniques , allele , microarray , genetics , gene expression , computational biology , neuroscience , receptor , medicine , myeloid cells
Background:The sortilin-related receptor LDLR class A repeats containing (SORL1) gene has been implicated in both early and late onset Alzheimer’s disease (AD). Located on chromosome 11q23.2-q24.2, SORL1 plays a key role in the differential sorting of the amyloid precursor protein (APP) and regulation of the amyloid-b (Ab) production. We describe the clinical and molecular findings among individuals with AD who present with SORL1 mutations. Methods:SORL1 changes were initially identified by whole exome sequencing in 50 early onset AD families with at least one case with onset <60 years of age. The clinical consequences associated with SORL1 mutations were characterized based on extensive clinical reviews of medical records. Functional studies were completed to evaluate Ab production and APP trafficking associated with SORL1mutations. Constructs were generated using human SORL1-MYC pcDNA3.1. Site directed mutagenesis was used to insert the T588I and T2134IM mutations verified by sequencing, and either the wild type or mutant constructs transfected into HEK293 cells expressing the Swedish APP mutant (APPsw). Cell culture and transfection followed previously described standard protocols. Ab, Western blot, and co-immunoprecipitation assays were performed. Results: A novel SORL1 T588I change was identified four individuals with AD from one family; a second family was found to carry the T2134 alteration in three of four AD cases. Two cases with the SORL1 T588I alteration also presented with Parkinsonian features; one case with the T2134M variant was identified postmortem to have Lewy bodies. Examination of unrelated patients with late onset AD (onset >65 years) identified four additional individuals with either SORL1 A528T or T947M alterations who also presented with Parkinsonian features. Functional studies demonstrate that the variants weaken the interaction of SORL1with full-length APP, resulting in altered levels of Ab and interfering with APP trafficking. Conclusions: The findings from this study support an important role for SORL1 mutations in AD pathogenesis by way of altering Ab levels and interfering with APP trafficking. In addition. the results point to a potential association of SORL1 in the manifestation of Parkinsonian features among individuals with AD, thus expanding the pheotypic spectrum of SORL1 mutations.