- Email: [email protected]
THE INFLUENCE OF AMYLOID-B PRECURSOR PROTEIN PROTEOLYTIC PROCESSING ON NEURONAL IRON HOMEOSTASIS
Poster Presentations: Tuesday, July 18, 2017 P3-151
VITAMIN D-RELATED VASCULAR INJURY IN ALZHEIMER’S DISEASE
Wei-Ju Lee1,2, Jong-Ling Fuh1,3, Jung-Lung Hsu4, ShuuJiun Wang1,3, 1National Yang-Ming University Schools of Medicine, Taipei, Taiwan; 2Taichung Veterans General Hospital, Taichung, Taiwan; 3Taipei Veterans General Hospital, Taipei, Taiwan; 4Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan, Taiwan. Contact e-mail: [email protected] Background: Reduced plasma 25-hydroxyvitamin D (25-OH-D)
was proved to be associated with poorer cognitive function and a higher risk of developing Alzheimer’s disease (AD), but the specific mechanisms were unknown. Increased vascular injury due to activation of renin-angiotensin-system is one of the hypotheses about the relationship between vitamin D and AD. Methods: We recruited patients with early AD from two teaching hospitals in Taiwan. All patients underwent clinically functional assessment and a neuropsychological test battery. Plasma 25-OH-D level was checked by radioimmunoassay. Brain magnetic resonance imaging (MRI) was used to determine the volume of white matter hyperintensities (WMH), a surrogate of cerebral vascular injury. We analyzed the relationship between cognitive function, plasma level of 25-OHD, and WMH volume in early AD patients. Results: In total, 146 early AD patients (68 males/78 females; mean age 79.1 6 7.0 years; mean education 10.2 6 4.3 years) were recruited. Their mean Mini-Mental State Examination (MMSE) was 21.0 6 3.8. The clinical dementia rating (CDR) score was 0.5 in 24 patients and 1.0 in 123 patients. The percentage of APOE ε4 carrier was 35.4 %. The correlation analysis between WMH volume and 25OH-D level showed significant negative correlation (R2 ¼ 0.086, adjusted p ¼ 0.003, adjusting age, sex, hypertension, diabetes mellitus, hyperlipidemia, and coronary heart disease). The correlation analysis between MMSE and 25-OH-D level showed significant positive correlation (R2 ¼ 0.067, adjusted p ¼ 0.002, adjusting age, sex, and education years). Multivariate regression analysis, performed by using MMSE as the dependent variable and adjusting age, sex, and education years, showed 25-OH-D level was an independent predictor for MMSE score (b ¼ 0.25, p ¼ 0.003), but WMH volume was not (b ¼ -0.02, p ¼ 0.82). Conclusions: Reduced plasma 25-OH-D was associated with low MMSE scores in early AD patients. The underlying mechanisms were partially attributed to cerebral vascular injury, and it also suggested the presence of other different mechanisms.
P3-152
THE ROLE OF AKT IN AGING-RELATED IMPAIRMENT
YuRu Chen1, HsuehCheng Chiang2, 1National Cheng Kung University, Tainan, Taiwan; 2National Cheng Kung University, Tainan City, Taiwan. Contact e-mail: [email protected] Background: Aging is considered as an irreversible process resulting
in physiological degeneration and dysfunction. It is also the major risking factor of degenerative diseases, like Alzheimer’s disease (AD). As the cost of social and economic expense on the care of senior people and patient of AD is increased worldwide, there is a growing need to understand and prevent aging process and medicine to treat related impairment. However, the detailed molecular mechanism involved in aging process still remained elusive. Methods: Using Drosophila melanogaster as a model system, we revealed that there is increased of AKT activity in the aging animal. Results: Overexpressed AKT in the brain reduces lifespan and jeopardize the learning ability. Reduced AKT level in the neurons re-
P993
verses aging-induced learning deficit and prolonged the survival rate in the aging-related stress condition. Pharmacological application to inhibit AKT activity improves life-span shortening in the AD animal. Our data further suggested that AKT signaling in the specific neurons plays different role in mediating aging-related stress condition, which suggests that aging-related impairments are triggered by different degenerated neurons. Finally, we showed that FOXO is the major downstream protein of AKT signaling to improve the lifespan and reverse the learning deficit in the AD animal. Conclusions: Our data demonstrate that AKT plays a crucial role in mediating aging-related impairments and AD pathogenesis, which suggest that there is a common molecular mechanism involved in aging process and AD.
P3-153
THE INFLUENCE OF AMYLOID-B PRECURSOR PROTEIN PROTEOLYTIC PROCESSING ON NEURONAL IRON HOMEOSTASIS
Bruce X. Wong1,2, Andrew Tsatsanis1, Linh Q. Lam2,3, Scott Ayton2,3, Adam P. Gunn2,4, David Devos4, Ashley I. Bush2,3, James A. Duce1,2,3, 1 The University of Leeds, Leeds, United Kingdom; 2The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; 3The University of Melbourne, Melbourne, Australia; 4Lille University, Lille, France. Contact e-mail: [email protected] Background: Intraneuronal iron imbalance is a predominant catalyst
for reactive oxygen species production, particularly within iron accumulating neurodegenerative diseases such as Alzheimer’s disease (AD). In AD, amyloid precursor protein (APP) has historically been associated with amyloid-b (Ab) derived neurotoxicity, but we recently discovered that APP also has a role in neuronal iron homeostasis by, in part, promoting iron efflux through cell surface stabilization of the iron pore ferroportin. Methods: The processing of APP was modified in cultured cells by secretase inhibition (TAPI or bIV) or depletion (ADAM10 or BACE1 siRNAi) in the presence (addition to media) or absence (chelation by deferiprone) of iron. Alternatively, iron homeostasis in N2A transfected with familiar APP mutations was also investigated. Cell surface biotinylation and fluorescence-activated cell sorting were used to examine changes in surface presented iron-associated proteins. Labile iron was measured by Calcein-AM and iron associated proteins were investigated through Western analysis. Results: Detailed cell surface characterization confirms that the location of ferroportin on the neuron surface is increased upon iron incubation and is dependent upon APP. Altering the proteolytic processing of APP at the cell surface by suppressing secretase expression or activity, or by manipulating expression of APP carrying familial AD mutations, causes consequential changes in neuronal iron homeostasis. Enhancing the amyloidogenic pathway of APP processing leads to intracellular iron accumulation. Conclusions: With increased amyloidogenic processing of APP being a major contributor to sporadic AD, these studies increase our understanding as to why iron accumulation and increased susceptibility to reactive oxygen species neurotoxicity are prevalent with the disease. P3-154
MOLECULAR MECHANISMS OF b-AMYLOID-INDUCED INHIBITION OF GLUTATHIONE SYNTHESIS IN RATS
Min Liu, Jing Cui, Guowen Min, Dandan Cao, Liang Li, Capital Medical University, Beijing, China. Contact e-mail: liliang8698@ yeah.net
VITAMIN D-RELATED VASCULAR INJURY IN ALZHEIMER’S DISEASE
Wei-Ju Lee1,2, Jong-Ling Fuh1,3, Jung-Lung Hsu4, ShuuJiun Wang1,3, 1National Yang-Ming University Schools of Medicine, Taipei, Taiwan; 2Taichung Veterans General Hospital, Taichung, Taiwan; 3Taipei Veterans General Hospital, Taipei, Taiwan; 4Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan, Taiwan. Contact e-mail: [email protected] Background: Reduced plasma 25-hydroxyvitamin D (25-OH-D)
was proved to be associated with poorer cognitive function and a higher risk of developing Alzheimer’s disease (AD), but the specific mechanisms were unknown. Increased vascular injury due to activation of renin-angiotensin-system is one of the hypotheses about the relationship between vitamin D and AD. Methods: We recruited patients with early AD from two teaching hospitals in Taiwan. All patients underwent clinically functional assessment and a neuropsychological test battery. Plasma 25-OH-D level was checked by radioimmunoassay. Brain magnetic resonance imaging (MRI) was used to determine the volume of white matter hyperintensities (WMH), a surrogate of cerebral vascular injury. We analyzed the relationship between cognitive function, plasma level of 25-OHD, and WMH volume in early AD patients. Results: In total, 146 early AD patients (68 males/78 females; mean age 79.1 6 7.0 years; mean education 10.2 6 4.3 years) were recruited. Their mean Mini-Mental State Examination (MMSE) was 21.0 6 3.8. The clinical dementia rating (CDR) score was 0.5 in 24 patients and 1.0 in 123 patients. The percentage of APOE ε4 carrier was 35.4 %. The correlation analysis between WMH volume and 25OH-D level showed significant negative correlation (R2 ¼ 0.086, adjusted p ¼ 0.003, adjusting age, sex, hypertension, diabetes mellitus, hyperlipidemia, and coronary heart disease). The correlation analysis between MMSE and 25-OH-D level showed significant positive correlation (R2 ¼ 0.067, adjusted p ¼ 0.002, adjusting age, sex, and education years). Multivariate regression analysis, performed by using MMSE as the dependent variable and adjusting age, sex, and education years, showed 25-OH-D level was an independent predictor for MMSE score (b ¼ 0.25, p ¼ 0.003), but WMH volume was not (b ¼ -0.02, p ¼ 0.82). Conclusions: Reduced plasma 25-OH-D was associated with low MMSE scores in early AD patients. The underlying mechanisms were partially attributed to cerebral vascular injury, and it also suggested the presence of other different mechanisms.
P3-152
THE ROLE OF AKT IN AGING-RELATED IMPAIRMENT
YuRu Chen1, HsuehCheng Chiang2, 1National Cheng Kung University, Tainan, Taiwan; 2National Cheng Kung University, Tainan City, Taiwan. Contact e-mail: [email protected] Background: Aging is considered as an irreversible process resulting
in physiological degeneration and dysfunction. It is also the major risking factor of degenerative diseases, like Alzheimer’s disease (AD). As the cost of social and economic expense on the care of senior people and patient of AD is increased worldwide, there is a growing need to understand and prevent aging process and medicine to treat related impairment. However, the detailed molecular mechanism involved in aging process still remained elusive. Methods: Using Drosophila melanogaster as a model system, we revealed that there is increased of AKT activity in the aging animal. Results: Overexpressed AKT in the brain reduces lifespan and jeopardize the learning ability. Reduced AKT level in the neurons re-
P993
verses aging-induced learning deficit and prolonged the survival rate in the aging-related stress condition. Pharmacological application to inhibit AKT activity improves life-span shortening in the AD animal. Our data further suggested that AKT signaling in the specific neurons plays different role in mediating aging-related stress condition, which suggests that aging-related impairments are triggered by different degenerated neurons. Finally, we showed that FOXO is the major downstream protein of AKT signaling to improve the lifespan and reverse the learning deficit in the AD animal. Conclusions: Our data demonstrate that AKT plays a crucial role in mediating aging-related impairments and AD pathogenesis, which suggest that there is a common molecular mechanism involved in aging process and AD.
P3-153
THE INFLUENCE OF AMYLOID-B PRECURSOR PROTEIN PROTEOLYTIC PROCESSING ON NEURONAL IRON HOMEOSTASIS
Bruce X. Wong1,2, Andrew Tsatsanis1, Linh Q. Lam2,3, Scott Ayton2,3, Adam P. Gunn2,4, David Devos4, Ashley I. Bush2,3, James A. Duce1,2,3, 1 The University of Leeds, Leeds, United Kingdom; 2The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; 3The University of Melbourne, Melbourne, Australia; 4Lille University, Lille, France. Contact e-mail: [email protected] Background: Intraneuronal iron imbalance is a predominant catalyst
for reactive oxygen species production, particularly within iron accumulating neurodegenerative diseases such as Alzheimer’s disease (AD). In AD, amyloid precursor protein (APP) has historically been associated with amyloid-b (Ab) derived neurotoxicity, but we recently discovered that APP also has a role in neuronal iron homeostasis by, in part, promoting iron efflux through cell surface stabilization of the iron pore ferroportin. Methods: The processing of APP was modified in cultured cells by secretase inhibition (TAPI or bIV) or depletion (ADAM10 or BACE1 siRNAi) in the presence (addition to media) or absence (chelation by deferiprone) of iron. Alternatively, iron homeostasis in N2A transfected with familiar APP mutations was also investigated. Cell surface biotinylation and fluorescence-activated cell sorting were used to examine changes in surface presented iron-associated proteins. Labile iron was measured by Calcein-AM and iron associated proteins were investigated through Western analysis. Results: Detailed cell surface characterization confirms that the location of ferroportin on the neuron surface is increased upon iron incubation and is dependent upon APP. Altering the proteolytic processing of APP at the cell surface by suppressing secretase expression or activity, or by manipulating expression of APP carrying familial AD mutations, causes consequential changes in neuronal iron homeostasis. Enhancing the amyloidogenic pathway of APP processing leads to intracellular iron accumulation. Conclusions: With increased amyloidogenic processing of APP being a major contributor to sporadic AD, these studies increase our understanding as to why iron accumulation and increased susceptibility to reactive oxygen species neurotoxicity are prevalent with the disease. P3-154
MOLECULAR MECHANISMS OF b-AMYLOID-INDUCED INHIBITION OF GLUTATHIONE SYNTHESIS IN RATS
Min Liu, Jing Cui, Guowen Min, Dandan Cao, Liang Li, Capital Medical University, Beijing, China. Contact e-mail: liliang8698@ yeah.net