- Email: [email protected]
THE ROLE OF AQUAPORIN-4 (AQP4) SINGLE NUCLEOTIDE POLYMORPHISMS IN COGNITIVE DECLINE
P1036
Poster Presentations: Wednesday, July 27, 2016
white matter lesions (WML), a risk factor for vascular cognitive impairment (VCI). Several studies show that carriers of the Met allele have reduced cognition, memory, and smaller hippocampal volume compared to Val/Val carriers. However, other studies have failed to find this or have found the opposite. These equivocal findings may be related to the interaction between BDNF polymorphism and biological sex. For example, the Met allele confers increased risk for dementia in females, but not males. Thus, we examined whether biological sex interacts with BDNF polymorphism to influence brain health. Methods: We conducted a secondary analysis of cognitive and neuroimaging data from the control arm of a 6-month single-blind randomized controlled trial of aerobic exercise in older adults with subcortical VCI, a population at high risk of progression to dementia. Executive processes were measured at baseline and 6-months using: 1) Trail Making Test (TMT; set-shifting); 2) Digit Symbol Substitution Test (DSST; sustained-attention); 3) Stroop Test (selective-attention, conflict resolution). Total WML (mm3) were quantified at baseline using a semiautomated analysis pipeline. BDNF genotyping was performed with a TaqMan by-design assay. Results: Over the 6 month period, Met carriers performed better on the TMT and the DSST compared to Val/Val carriers in females only. Among Val/Val carriers, males outperformed females on the TMT. Among Met carriers, females outperformed males on the DSST. Performance on the Stroop was not significantly impacted by sex or genotype. In females, Met carriers tended to have greater WML load than Val/Val carriers, and the opposite was seen in males. Among Val/Val carriers, males had greater WML load at baseline than females. Conclusions: Our study provides new knowledge about how biological sex can interact with genotype to alter brain health in older adults at risk for dementia. Future studies will examine whether the BDNF polymorphism moderates exercise efficacy on cognitive health in a sexdependent manner. P4-056
THE ROLE OF AQUAPORIN-4 (AQP4) SINGLE NUCLEOTIDE POLYMORPHISMS IN COGNITIVE DECLINE
Kevin G. Burfeind, Charles F. Murchison, Shawn K. Westaway, Deniz Erten-Lyons, Jeff A. Kaye, Joseph F. Quinn, Jeffrey J. Iliff, Oregon Health & Science University, Portland, OR, USA. Contact e-mail: [email protected] Background: The glymphatic system is a brain-wide perivascular
network that facilitates clearance of proteins, including amyloid beta, from the brain interstitium. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, yet whether changes in AQP4 function influence development of agerelated cognitive decline or Alzheimer’s disease (AD) is not known. We identified five noncoding single nucleotide polymorphisms (SNPs) in the human AQP4 gene that were associated with altered cognitive decline after AD diagnosis. Methods: Using genetic and longitudinal neurocognitive data from 794 elderly participants from the NIA - Oregon Alzheimer’s Disease Center cohorts (512 cognitively intact, 124 mild cognitive impairment, and 158 AD at first visit) the association between five human AQP4 SNPs and rate of cognitive decline (using the Mini Mental State Examination (MMSE)) and dementia progression (using the Clinical Dementia Rating (CDR)) scale was evaluated. Data analysis was carried out using linear mixedmodeling to evaluate the associations of minor SNP alleles with altered longitudinal rates of cognitive decline. Results: Of the five SNPs, three were associated with slower cognitive decline or dementia progression after AD diagnosis, and two were associated with faster
cognitive decline or dementia progression after AD diagnosis. Heterozygous or homozygous possession of the minor allele at position rs9951307 (genotype TC or TT) was associated with slower increase in CDR sum of the boxes score (t¼-4.31, p<0.001), while rs335929 (genotype CA or CC) was associated with slower decline in MMSE score (t¼3.46, p<0.001), and rs387509 (genotype TC or CC) was associated with both slower decline in MMSE score (t¼2.66, p¼0.008) and slower increase in CDR score (t¼-4.80, p<0.001). rs3763043 (genotype GA or GG) was associated with faster decline in MMSE (t¼-3.29, p<0.001) and faster increase in CDR score (t¼4.00, p<0.001). rs3763040 (genotype AG or AA) was also associated with faster decline in MMSE (t¼-5.28, p<0.001) and faster increase in CDR score (t¼3.70, p<0.001). Conclusions: These results suggest that variations in the AQP4 gene, which plays a vital role in the glymphatic pathway, may modulate the progression of cognitive decline and dementia in AD. This may provide a novel therapeutic target for the prevention or treatment of AD. P4-057
EFFICACY OF FLUORESCENCE-LABELLED AMYLOID-BETA1-42 ON MICROGLIAL ACTIVATION
Ling Guo, The Third People’s Hospital of Yunnan Province, Kunming, China. Contact e-mail: [email protected] Background: We have shown that the aged primate brain is selec-
tively volunable to regular fibrillar Ab toxicity. Based on what we have found in primate, it is necessary to explore the capabilities of fibrillar fluorescence-labelled Ab1-42 to microglia derived from aged postmortem human brains and to know whether and how human microglial cultures respond to different preparations of fibrillar Ab. Previous studies have also demonstrated that regular Ab1-42 induced microglial activation and released active biochemical factors such as reactive oxygen species (ROS) or cytokines in vitro. However, whether the effecacy of fluorescence-labelled Ab1-42 fibrils on microglial activation is same as that of regular Ab1-42 (non-labelled) or not still remains unknown. To ensure the concern, we set up some experiments to explore it. Methods: Aging fluorescence-labelled Ab1-42 (AnaSpec, Cat#24224) and regular Ab1-42 (BACHEM, Cat#H-1368) at 37 C for 4 days to form fibrillary Ab142 at 100uM. Primary human microglia were isolated from postmortem brains of Alzheimer’s disease and grown for several passages. SY5Y cells as a neuronal cell line were grown for paralleled experiments. To compare the effercacy of the two fibrillars of Ab1-42, the cultures were split and plated into 8-chamber slides or 48-well plates, and the preparations of fibrillar Ab1-42 was treated to the cells for 24 hours. Reactive oxygen species (ROS), TNF-a, and degenerative neuronal cells were measured via NBT assay, ELISA, and Trypan Blue staining. Results: Fibrillar preparations of fluorescence-labelled Ab1-42 (AnaSpec, Cat#24224) or regular Ab1-42 (BACHEM, Cat#H-1368) induced production of ROS increase, and neuronal killing through activated microglia. Exposed primary human microglia to the two preps for 24 hours, after exposuring SY5Y cells to the medium of activated microglia induced by the two different types of Ab1-42 fibrils for 24 hours, SY5Y cells were stained blue by trypan blue, which indicated the degeneration. Conclusions: Fluorescence-labelled Ab1-42 fibrils could make primary human microglia activated. The efficacy of this preparation on ROS was slightly lower than that of the nonlabelled Ab1-42 fibrils. SY5Y neuronal cells could be killed by the activated microglial cultures induced by the fibrillar Ab1-42 or directly by the two types of fibrils.
Poster Presentations: Wednesday, July 27, 2016
white matter lesions (WML), a risk factor for vascular cognitive impairment (VCI). Several studies show that carriers of the Met allele have reduced cognition, memory, and smaller hippocampal volume compared to Val/Val carriers. However, other studies have failed to find this or have found the opposite. These equivocal findings may be related to the interaction between BDNF polymorphism and biological sex. For example, the Met allele confers increased risk for dementia in females, but not males. Thus, we examined whether biological sex interacts with BDNF polymorphism to influence brain health. Methods: We conducted a secondary analysis of cognitive and neuroimaging data from the control arm of a 6-month single-blind randomized controlled trial of aerobic exercise in older adults with subcortical VCI, a population at high risk of progression to dementia. Executive processes were measured at baseline and 6-months using: 1) Trail Making Test (TMT; set-shifting); 2) Digit Symbol Substitution Test (DSST; sustained-attention); 3) Stroop Test (selective-attention, conflict resolution). Total WML (mm3) were quantified at baseline using a semiautomated analysis pipeline. BDNF genotyping was performed with a TaqMan by-design assay. Results: Over the 6 month period, Met carriers performed better on the TMT and the DSST compared to Val/Val carriers in females only. Among Val/Val carriers, males outperformed females on the TMT. Among Met carriers, females outperformed males on the DSST. Performance on the Stroop was not significantly impacted by sex or genotype. In females, Met carriers tended to have greater WML load than Val/Val carriers, and the opposite was seen in males. Among Val/Val carriers, males had greater WML load at baseline than females. Conclusions: Our study provides new knowledge about how biological sex can interact with genotype to alter brain health in older adults at risk for dementia. Future studies will examine whether the BDNF polymorphism moderates exercise efficacy on cognitive health in a sexdependent manner. P4-056
THE ROLE OF AQUAPORIN-4 (AQP4) SINGLE NUCLEOTIDE POLYMORPHISMS IN COGNITIVE DECLINE
Kevin G. Burfeind, Charles F. Murchison, Shawn K. Westaway, Deniz Erten-Lyons, Jeff A. Kaye, Joseph F. Quinn, Jeffrey J. Iliff, Oregon Health & Science University, Portland, OR, USA. Contact e-mail: [email protected] Background: The glymphatic system is a brain-wide perivascular
network that facilitates clearance of proteins, including amyloid beta, from the brain interstitium. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, yet whether changes in AQP4 function influence development of agerelated cognitive decline or Alzheimer’s disease (AD) is not known. We identified five noncoding single nucleotide polymorphisms (SNPs) in the human AQP4 gene that were associated with altered cognitive decline after AD diagnosis. Methods: Using genetic and longitudinal neurocognitive data from 794 elderly participants from the NIA - Oregon Alzheimer’s Disease Center cohorts (512 cognitively intact, 124 mild cognitive impairment, and 158 AD at first visit) the association between five human AQP4 SNPs and rate of cognitive decline (using the Mini Mental State Examination (MMSE)) and dementia progression (using the Clinical Dementia Rating (CDR)) scale was evaluated. Data analysis was carried out using linear mixedmodeling to evaluate the associations of minor SNP alleles with altered longitudinal rates of cognitive decline. Results: Of the five SNPs, three were associated with slower cognitive decline or dementia progression after AD diagnosis, and two were associated with faster
cognitive decline or dementia progression after AD diagnosis. Heterozygous or homozygous possession of the minor allele at position rs9951307 (genotype TC or TT) was associated with slower increase in CDR sum of the boxes score (t¼-4.31, p<0.001), while rs335929 (genotype CA or CC) was associated with slower decline in MMSE score (t¼3.46, p<0.001), and rs387509 (genotype TC or CC) was associated with both slower decline in MMSE score (t¼2.66, p¼0.008) and slower increase in CDR score (t¼-4.80, p<0.001). rs3763043 (genotype GA or GG) was associated with faster decline in MMSE (t¼-3.29, p<0.001) and faster increase in CDR score (t¼4.00, p<0.001). rs3763040 (genotype AG or AA) was also associated with faster decline in MMSE (t¼-5.28, p<0.001) and faster increase in CDR score (t¼3.70, p<0.001). Conclusions: These results suggest that variations in the AQP4 gene, which plays a vital role in the glymphatic pathway, may modulate the progression of cognitive decline and dementia in AD. This may provide a novel therapeutic target for the prevention or treatment of AD. P4-057
EFFICACY OF FLUORESCENCE-LABELLED AMYLOID-BETA1-42 ON MICROGLIAL ACTIVATION
Ling Guo, The Third People’s Hospital of Yunnan Province, Kunming, China. Contact e-mail: [email protected] Background: We have shown that the aged primate brain is selec-
tively volunable to regular fibrillar Ab toxicity. Based on what we have found in primate, it is necessary to explore the capabilities of fibrillar fluorescence-labelled Ab1-42 to microglia derived from aged postmortem human brains and to know whether and how human microglial cultures respond to different preparations of fibrillar Ab. Previous studies have also demonstrated that regular Ab1-42 induced microglial activation and released active biochemical factors such as reactive oxygen species (ROS) or cytokines in vitro. However, whether the effecacy of fluorescence-labelled Ab1-42 fibrils on microglial activation is same as that of regular Ab1-42 (non-labelled) or not still remains unknown. To ensure the concern, we set up some experiments to explore it. Methods: Aging fluorescence-labelled Ab1-42 (AnaSpec, Cat#24224) and regular Ab1-42 (BACHEM, Cat#H-1368) at 37 C for 4 days to form fibrillary Ab142 at 100uM. Primary human microglia were isolated from postmortem brains of Alzheimer’s disease and grown for several passages. SY5Y cells as a neuronal cell line were grown for paralleled experiments. To compare the effercacy of the two fibrillars of Ab1-42, the cultures were split and plated into 8-chamber slides or 48-well plates, and the preparations of fibrillar Ab1-42 was treated to the cells for 24 hours. Reactive oxygen species (ROS), TNF-a, and degenerative neuronal cells were measured via NBT assay, ELISA, and Trypan Blue staining. Results: Fibrillar preparations of fluorescence-labelled Ab1-42 (AnaSpec, Cat#24224) or regular Ab1-42 (BACHEM, Cat#H-1368) induced production of ROS increase, and neuronal killing through activated microglia. Exposed primary human microglia to the two preps for 24 hours, after exposuring SY5Y cells to the medium of activated microglia induced by the two different types of Ab1-42 fibrils for 24 hours, SY5Y cells were stained blue by trypan blue, which indicated the degeneration. Conclusions: Fluorescence-labelled Ab1-42 fibrils could make primary human microglia activated. The efficacy of this preparation on ROS was slightly lower than that of the nonlabelled Ab1-42 fibrils. SY5Y neuronal cells could be killed by the activated microglial cultures induced by the fibrillar Ab1-42 or directly by the two types of fibrils.