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Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease.

ABSTRACT: A rare amyloid precursor protein gene variant, A673T (rs63750847) was recently reported to protect against Alzheimer's disease and age-related cognitive decline among Icelanders and the same rare variant was observed also in Finnish, Norwegian, and Swedish populations. We investigated this variant in 1674 late-onset Alzheimer's disease cases and 2644 elderly control subjects, all North American Whites (US Whites). We did not observe any example of the A673T variant in our large sample. Our findings suggest that this rare variant could be specific to the individuals of the origin from the Nordic countries.

SUBMITTER: Bamne MN

PROVIDER: S-EPMC4009010 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease.

Bamne Mikhil N MN Demirci F Yesim FY Berman Sarah S Snitz Beth E BE Rosenthal Samantha L SL Wang Xingbin X Lopez Oscar L OL Kamboh M Ilyas MI

Neurobiology of aging 20140123 7

A rare amyloid precursor protein gene variant, A673T (rs63750847) was recently reported to protect against Alzheimer's disease and age-related cognitive decline among Icelanders and the same rare variant was observed also in Finnish, Norwegian, and Swedish populations. We investigated this variant in 1674 late-onset Alzheimer's disease cases and 2644 elderly control subjects, all North American Whites (US Whites). We did not observe any example of the A673T variant in our large sample. Our findi ...[more]

PMID: 24529499

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Project description:Pathogenic mutations in the amyloid precursor protein (APP) gene have been described as causing early onset familial Alzheimer disease (AD). We recently identified a rare APP variant encoding an alanine-to-threonine substitution at residue 673 (A673T) that confers protection against development of AD (Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., Hoyte, K., Gustafson, A., Liu, Y., Lu, Y., Bhangale, T., Graham, R. R., Huttenlocher, J., Bjornsdottir, G., Andreassen, O. A., Jönsson, E. G., Palotie, A., Behrens, T. W., Magnusson, O. T., Kong, A., Thorsteinsdottir, U., Watts, R. J., and Stefansson, K. (2012) Nature 488, 96-99). The Ala-673 residue lies within the ?-secretase recognition sequence and is part of the amyloid-? (A?) peptide cleavage product (position 2 of A?). We previously demonstrated that the A673T substitution makes APP a less favorable substrate for cleavage by BACE1. In follow-up studies, we confirm that A673T APP shows reduced cleavage by BACE1 in transfected mouse primary neurons and in isogenic human induced pluripotent stem cell-derived neurons. Using a biochemical approach, we show that the A673T substitution modulates the catalytic turnover rate (V(max)) of APP by the BACE1 enzyme, without affecting the affinity (K(m)) of the APP substrate for BACE1. We also show a reduced level of A?(1-42) aggregation with A2T A? peptides, an observation not conserved in A?(1-40) peptides. When combined in a ratio of 1:9 A?(1-42)/A?(1-40) to mimic physiologically relevant mixtures, A2T retains a trend toward slowed aggregation kinetics. Microglial uptake of the mutant A?(1-42) peptides correlated with their aggregation level. Cytotoxicity of the mutant A? peptides was not dramatically altered. Taken together, our findings demonstrate that A673T, a protective allele of APP, reproducibly reduces amyloidogenic processing of APP and also mildly decreases A? aggregation. These effects could together have an additive or even synergistic impact on the risk of developing AD.

Project description:BackgroundAdult ADHD has been assumed to be a continuation of childhood-onset ADHD. However, recent studies have identified individuals with ADHD in adulthood who have not had ADHD in childhood. Whether or not these individuals have a 'typical' neurodevelopmental profile is not clear.MethodsWe tested two explanations for the emergence of apparent late-onset ADHD symptomatology using the ALSPAC epidemiological cohort, by grouping individuals according to their scores on the Strengths and Difficulties Questionnaire (SDQ) hyperactivity subscale at ages 12 and 17 years. First, we tested whether some of those with apparent late-onset ADHD symptoms had been potentially misclassified on the basis of earlier SDQ hyperactivity scores (ages 7, 8 and 9 years) or of subthreshold symptoms at age 12 years. Second, we investigated the possibility that those with 'genuine' late-onset ADHD symptoms had a delayed manifestation of the same liability that underlies childhood-onset symptoms, by investigating whether they had a similar profile of neurodevelopmental impairments (in the domains of autistic symptomatology, language, reading, spelling, executive functioning and IQ) as those with typical childhood-onset ADHD.ResultsN = 56/75 (75%) of those with apparent late-onset ADHD had had high ADHD scores at least one point in childhood, suggesting that they may have been misclassified on the basis of their score at age 12 years. The remaining 19 individuals (25%) with genuine late-onset ADHD symptoms did not show a profile of neurodevelopmental impairment typically seen in ADHD, instead showing similar levels of autistic symptoms, language skills, executive functioning ability and IQ to those without ADHD symptoms. The only exceptions were that this group showed reading and spelling problems at age 9 years.ConclusionsOur work suggests that this small number of individuals with genuine late-onset symptoms may not be most appropriately considered as having a typical neurodevelopmental disorder.

Dataset Information

Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease.

Publications

Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease.

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