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J Alzheimers Dis. 2019;69(1):199-212. doi: 10.3233/JAD-181291.

A Novel PSEN1 M139L Mutation Found in a Chinese Pedigree with Early-Onset Alzheimer's Disease Increases Aβ42/Aβ40 ratio.

Qiu Q1, Shen L1, Jia L1,2,3,4,5,6, Wang Q1,2,3,4,5,6, Li F1,2,3,4,5,6, Li Y1,2,3,4,5,6, Jia J1,2,3,4,5,6.

Author information

Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, P.R. Beijing, China.
Beijing Key Laboratory of Geriatric Cognitive Disorders, P.R. Beijing, China.
Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, P.R. Beijing, China.
Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China.
Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, P.R. China.
National Clinical Research Center for Geriatric Disorders, Beijing, P.R. China.



Presenilin1 (PSEN1) is the most common gene related to familial Alzheimer's disease (AD). Only several mutation types from Chinese have been reported, with less biological function research conducted.


We explore the pathological function of PSEN1 M139L, a mutation located at α-helix of PSEN1 transmembrane 2, using predictive programs and in vitro study and compare its effects on Aβ production to those of an artificial PSEN1 S141G located at non α-helix mutation face.


APP, PSEN1, and PSEN2 genes were screened for mutations using Sanger sequencing in the DNA samples of the proband and additional available family members. Disease-mutation cosegregation analysis and three software programs were performed to predict the mutation's pathogenicity. In vitro, we investigated the impact of these mutations on Aβ production in HEK293-APPswe cells using lentiviral vectors harboring PSEN1 WT, PSEN1 M139L, the positive control (PSEN1 M139V) and the non α-helical mutation (PSEN1 S141G). In addition, we co-transfected PSEN1 and tau into cells to determine the mutations' impact on tau phosphorylation.


PSEN1 M139L mutation was discovered in the index patient and four affected siblings. Cosegregation analysis and silicon prediction suggested the mutation was probably disease causing. In vitro studies demonstrated that both PSEN1 M139L and PSEN1 S141G caused elevated ratios of Aβ42/Aβ40, but changes of tau phosphorylation were not detected.


The novel PSEN1 M139L mutation found in familial AD increases the Aβ42/Aβ40 ratio significantly. Mutations at non α-helical mutation face of PSEN1 TM2 can affect Aβ production and the region may play a key role in PSEN1 function.


Alzheimer’s disease; amyloid-β ; mutation; presenilin; α-helix


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