- Email: [email protected]
DIFFERENCES BETWEEN MEN AND WOMEN IN THE RISK OF DEMENTIA
Podium Presentations: Sunday, July 24, 2016
SUNDAY, JULY 24, 2016 SYMPOSIA S1-01 GENDER AND ALZHEIMER’S DISEASE S1-01-02
DIFFERENCES BETWEEN MEN AND WOMEN IN THE RISK OF DEMENTIA
Michelle M. Mielke, Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Abstract not available. S1-01-03
SEX-SPECIFIC DRIVERS OF ALZHEIMER’S DISEASE RISK AND RESILIENCE
Timothy J. Hohman, Vanderbilt University School of Medicine, Nashville, TN, USA. Contact e-mail: [email protected] Background: Women are disproportionately affected by Alzheimer’s disease (AD) and are more likely to manifest clinical symptoms in the presence of AD neuropathology. The goal of this project was to identify factors that differentially promote risk and resilience to cognitive impairment in men and women harboring biomarkers of AD neuropathology. Methods: Participants were drawn from the AD Neuroimaging Initiative and included participants with cerebrospinal fluid (CSF) biomarker data and either genotype data (n¼624) or additional proteomic data measured in CSF (n¼316). Mixed-effects regression models were leveraged to identify genetic and proteomic effects that differentially modified the association between CSF biomarkers of AD neuropathology and brain aging outcomes (i.e., hippocampal volume and cognition). Results: We identified multiple sex-specific single nucleotide polymorphism (SNP) effects including rs877399, a missense mutation within the toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP) gene. In the proteomic analysis, CSF sortilin levels modified the association between tau and hippocampal volume in women (p¼0.0003), but not in men (p¼0.840). Conclusions: Sex-specific drivers of the downstream consequences of AD neuropathology play an important role in the clinical manifestation of the disease. A more thorough understanding of sexspecific pathways of risk and resilience is needed to move towards personalized approaches to clinical intervention. S1-01-04
SEX DIFFERENCES IN THE BRAIN AND IMPLICATIONS FOR ALZHEIMER’S DISEASE 1
1
1
P161
tia (AD). Methods: In order to better understand the trajectory from oophorectomy and withdrawal of 17-beta-estradiol to cognitive decline, we recruited women with a high risk of breast and ovarian cancer (BRCA1/2 mutations) who had prophylacttc BSO before the age of natural menopause. We compared their performance on standard neuropsychological tests from 1 to 10 years post-BSO comparing it to the performance of women with the BRCA mutation but without BSO and to that of age-matched controls. Results: At the first time point of testing, compared to the controls who had not undergone oophorectomy, women with BSO recalled significantly fewer details on a paragraph recall task, on both the immediate and delayed trials. A significant group difference was also found on a composite measure of verbal memory in which women with BSO had the lowest average score. In addition, we found that years since surgery was a significant, negative predictor of performance on verbal fluency, or word retrieval, after controlling for age and education. Conclusions: Taken together, these results suggest that verbal memory and fluency are affected following BSO, underscoring the importance of ovarian steroids for women’s brain health.
SUNDAY, JULY 24, 2016 INVITED SPEAKERS EC-01 EMERGING CONCEPTS: SECRETASE BIOLOGY EC-01-01
TARGETING SECRETASES IN THE PRODROMAL, CELLULAR PHASE OF ALZHEIMER DISEASE
Bart De Strooper, VIB, KUL Center for the Biology of Disease, Leuven, Belgium; UCL Institute of Neurology, London, United Kingdom. Contact e-mail: [email protected]
Abstract not available. EC-01-02
STRUCTURE OF G-SECRETASES AND IMPLICATIONS FOR DRUG DEVELOPMENT
Xiao-chen Bai1, Eeson Rajendra1, Ganghui Yang2, Yigong Shi2, Sjors Scheres1, 1MRC Laboratory of Molecular Biology, Cambridge, United Kingdom; 2Tsinghua University, Beijing, China. Contact e-mail: [email protected] Background: Human g-secretase is an intra-membrane protease
2
Gillian Einstein , April Au , Deborah Schwartz , Elizabeth Hampson , Mary C. Tierney1, Wendy Meschino3, Andrea Eisen4, Amy Finch5, Joan Murphy6, Steven Narod5, 1University of Toronto, Toronto, ON, Canada; 2University of Western Ontario, London, ON, Canada; 3North York General Hospital, Toronto, ON, Canada; 4Sunnybrook Hospital, Toronto, ON, Canada; 5Women’s College Research Institute, Toronto, ON, Canada; 6 Princess Margaret Hospital, Toronto, ON, Canada. Contact e-mail: gillian. [email protected] Background: Estrogens have an effect on both female and male brains profoundly affecting growth of neuronal synapses and processes in the hippocampus with some evidence suggesting that the effects are different for each sex. For women, estrogen withdrawal has long been thought to be a risk factor for Alzheimer’s disease and related dementias with current epidemiological evidence showing that women with with bilateral salpingooophorectomy (BSO) prior to natural menopause (estimated at 300,000 per year in the U.S. alone) have a higher incidence of all causes of death including, Alzheimer’s demen-
that cleaves many different substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein lead to Alzheimer’s disease. Methods: We use cryo-EM structure determination to solve the atomic structure of human g-secretase, and develop novel image processing methods to sort out different structural states that describe its intrinsic dynamics. Results: We propose a near-complete atomic model of human g-secretase, and describe its interaction with the the dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-Lalanyl]-S-phenylglycine t-butyl ester (DAPT). In addition, we describe how the second transmembrane helix of presenilin is disordered in its apo-state, but becomes ordered upon binding of either DAPT or helical substrate-like molecules that co-purified with g-secretase. Conclusions: Our cryo-EM structures of human g-secretase provide detailed insights into how the four protein components come together to form this intra-membrane protease complex, and allow us to propose a model for how substrate is bound and how DAPT inhibits proteolysis.
SUNDAY, JULY 24, 2016 SYMPOSIA S1-01 GENDER AND ALZHEIMER’S DISEASE S1-01-02
DIFFERENCES BETWEEN MEN AND WOMEN IN THE RISK OF DEMENTIA
Michelle M. Mielke, Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Abstract not available. S1-01-03
SEX-SPECIFIC DRIVERS OF ALZHEIMER’S DISEASE RISK AND RESILIENCE
Timothy J. Hohman, Vanderbilt University School of Medicine, Nashville, TN, USA. Contact e-mail: [email protected] Background: Women are disproportionately affected by Alzheimer’s disease (AD) and are more likely to manifest clinical symptoms in the presence of AD neuropathology. The goal of this project was to identify factors that differentially promote risk and resilience to cognitive impairment in men and women harboring biomarkers of AD neuropathology. Methods: Participants were drawn from the AD Neuroimaging Initiative and included participants with cerebrospinal fluid (CSF) biomarker data and either genotype data (n¼624) or additional proteomic data measured in CSF (n¼316). Mixed-effects regression models were leveraged to identify genetic and proteomic effects that differentially modified the association between CSF biomarkers of AD neuropathology and brain aging outcomes (i.e., hippocampal volume and cognition). Results: We identified multiple sex-specific single nucleotide polymorphism (SNP) effects including rs877399, a missense mutation within the toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP) gene. In the proteomic analysis, CSF sortilin levels modified the association between tau and hippocampal volume in women (p¼0.0003), but not in men (p¼0.840). Conclusions: Sex-specific drivers of the downstream consequences of AD neuropathology play an important role in the clinical manifestation of the disease. A more thorough understanding of sexspecific pathways of risk and resilience is needed to move towards personalized approaches to clinical intervention. S1-01-04
SEX DIFFERENCES IN THE BRAIN AND IMPLICATIONS FOR ALZHEIMER’S DISEASE 1
1
1
P161
tia (AD). Methods: In order to better understand the trajectory from oophorectomy and withdrawal of 17-beta-estradiol to cognitive decline, we recruited women with a high risk of breast and ovarian cancer (BRCA1/2 mutations) who had prophylacttc BSO before the age of natural menopause. We compared their performance on standard neuropsychological tests from 1 to 10 years post-BSO comparing it to the performance of women with the BRCA mutation but without BSO and to that of age-matched controls. Results: At the first time point of testing, compared to the controls who had not undergone oophorectomy, women with BSO recalled significantly fewer details on a paragraph recall task, on both the immediate and delayed trials. A significant group difference was also found on a composite measure of verbal memory in which women with BSO had the lowest average score. In addition, we found that years since surgery was a significant, negative predictor of performance on verbal fluency, or word retrieval, after controlling for age and education. Conclusions: Taken together, these results suggest that verbal memory and fluency are affected following BSO, underscoring the importance of ovarian steroids for women’s brain health.
SUNDAY, JULY 24, 2016 INVITED SPEAKERS EC-01 EMERGING CONCEPTS: SECRETASE BIOLOGY EC-01-01
TARGETING SECRETASES IN THE PRODROMAL, CELLULAR PHASE OF ALZHEIMER DISEASE
Bart De Strooper, VIB, KUL Center for the Biology of Disease, Leuven, Belgium; UCL Institute of Neurology, London, United Kingdom. Contact e-mail: [email protected]
Abstract not available. EC-01-02
STRUCTURE OF G-SECRETASES AND IMPLICATIONS FOR DRUG DEVELOPMENT
Xiao-chen Bai1, Eeson Rajendra1, Ganghui Yang2, Yigong Shi2, Sjors Scheres1, 1MRC Laboratory of Molecular Biology, Cambridge, United Kingdom; 2Tsinghua University, Beijing, China. Contact e-mail: [email protected] Background: Human g-secretase is an intra-membrane protease
2
Gillian Einstein , April Au , Deborah Schwartz , Elizabeth Hampson , Mary C. Tierney1, Wendy Meschino3, Andrea Eisen4, Amy Finch5, Joan Murphy6, Steven Narod5, 1University of Toronto, Toronto, ON, Canada; 2University of Western Ontario, London, ON, Canada; 3North York General Hospital, Toronto, ON, Canada; 4Sunnybrook Hospital, Toronto, ON, Canada; 5Women’s College Research Institute, Toronto, ON, Canada; 6 Princess Margaret Hospital, Toronto, ON, Canada. Contact e-mail: gillian. [email protected] Background: Estrogens have an effect on both female and male brains profoundly affecting growth of neuronal synapses and processes in the hippocampus with some evidence suggesting that the effects are different for each sex. For women, estrogen withdrawal has long been thought to be a risk factor for Alzheimer’s disease and related dementias with current epidemiological evidence showing that women with with bilateral salpingooophorectomy (BSO) prior to natural menopause (estimated at 300,000 per year in the U.S. alone) have a higher incidence of all causes of death including, Alzheimer’s demen-
that cleaves many different substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein lead to Alzheimer’s disease. Methods: We use cryo-EM structure determination to solve the atomic structure of human g-secretase, and develop novel image processing methods to sort out different structural states that describe its intrinsic dynamics. Results: We propose a near-complete atomic model of human g-secretase, and describe its interaction with the the dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-Lalanyl]-S-phenylglycine t-butyl ester (DAPT). In addition, we describe how the second transmembrane helix of presenilin is disordered in its apo-state, but becomes ordered upon binding of either DAPT or helical substrate-like molecules that co-purified with g-secretase. Conclusions: Our cryo-EM structures of human g-secretase provide detailed insights into how the four protein components come together to form this intra-membrane protease complex, and allow us to propose a model for how substrate is bound and how DAPT inhibits proteolysis.