- Email: [email protected]
Brain-derived and synthetic Aβ aggregates are prions
P434
Oral Sessions: O3-04: Cellular and Molecular Mechanisms: Amyloid II
dementia are evident. Such a test may also support in drug development by enabling homogenous cohorts in the clinical trials reducing trial size and costs. In a proof of concept (PoC) study we identified a gene expression signature in blood that detected MCI progressing to AD (prodromal AD) in an MCI population. We have now undertaken additional studies to further investigate and develop this gene expression signature. Methods: Blood samples were obtained from the DiaGenic biobank that previously had been collected from DiaGenic’s multi-center blood collection studies in EU and the US. Total RNA was isolated from blood sampled in PAXgene“¢ tubes. Gene expression in blood was investigated using RT-qPCR on ViiA7 Dx (Life Technologies) for 384 TaqMan assays (384-assay cards) resulting in a quality approved dataset. Data modelling and analysis were performed using multivariate statistical methods. Results: In the previous PoC study we developed the first blood based prodromal AD gene expression biomarker based on an algorithm (model) using the gene expression information from 20 assays to predict MCI progressing to AD in an MCI population. The prediction accuracy of detecting prodromal AD was 74%, sensitivity 74% and specificity 75%. Now we present new results from additional studies on developing and evaluating this gene expression signature for prodromal AD. Conclusions: We have demonstrated that it is possible to detect individuals with MCI progressing to AD (prodromal AD) within 2 years from AD diagnosis based on analysis of gene expression in blood. The new results will increase our understanding of the utility of this potential diagnostic biomarker for prodromal AD. O3-03-06
COMPARISON OF BRIEF COGNITIVE TESTS AND CSF ANALYSIS IN PREDICTING ALZHEIMER’S DISEASE IN MILD COGNITIVE IMPAIRMENT: SIX-YEAR FOLLOW-UP STUDY
Sebastian Palmqvist1, Joakim Hertze1, Lennart Minthon1, Carina Wattmo1, Kaj Blennow2, Henrik Zetterberg2, Elisabet Londos1, Oskar Hansson3, 1Clinical Memory Research Unit, Lund University, Malm€o, Sweden; 2Clinical Neurochemistry Lab, Department of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, M€olndal, Sweden; 3Lund University, Malm€o, Sweden. Background: Early identification of Alzheimer’s disease (AD) is needed both for clinical trials and in clinical practice. In this study, we compared brief cognitive tests and cerebrospinal fluid (CSF) biomarkers in predicting conversion from mild cognitive impairment (MCI) to AD. Methods: At a memory clinic, 133 patients with MCI were followed until development of dementia or until they had been stable over a mean period of 5.9 years (range 3.2-8.8 years). The Mini-Mental State Examination (MMSE), the clock drawing test, total tau, tau phosphorylated at Thr181 (P-tau) and amyloid-b1-42 (Ab42) were assessed at baseline. Results: During clinical follow-up, 47% remained cognitively stable and 53% developed dementia, with an incidence of 13.8%/year. In the group that developed dementia, the prevalence of AD was 73.2% and the other dementias consisted mostly of vascular dementia. When predicting subsequent development of AD among patients with MCI, the cognitive tests classified 81% of the cases correctly (AUC, 0.85; 95% CI, 0.77-0.90) and CSF biomarkers 83% (AUC, 0.89; 95% CI, 0.82-0.94). The combination of cognitive tests and CSF biomarkers (AUC, 0.93; 95% CI 0.87 to 0.96) was significantly better than the cognitive tests (p¼0.01) and the CSF biomarkers (p¼0.04) alone when predicting AD. Conclusions: The MMSE and the clock drawing test were as accurate as CSF biomarkers in predicting future development of AD in patients with MCI. Combining both instruments provided significantly greater accuracy than cognitive tests or CSF biomarkers alone in predicting AD. ORAL SESSIONS: O3-04 CELLULAR AND MOLECULAR MECHANISMS: AMYLOID II O3-04-01
BRAIN-DERIVED AND SYNTHETIC Ab AGGREGATES ARE PRIONS
Jan Stoehr1, Joel Watts1, Zachary Mensinger1, Abby Oehler2, Sunny Grillo1, Stephen DeArmond2, Stanley Prusiner1, Kurt Giles3, 1Institute for
Neurodegenerative Diseases, UCSF, San Francisco, California, United States; 2Department of Pathology, UCSF, San Francisco, California, United States; 3UCSF, San Francisco, California, United States. Background: Aggregation of Ab in the brain is an early event in Alzheimer’s disease (AD), and therefore an ideal target for therapeutic intervention. This aggregation can be induced in susceptible transgenic (Tg) mice by inoculation with brain homogenate containing pre-formed Ab aggregates, suggesting that Ab aggregates are capable of self-propagation in a prionlike manner. We have recently shown that astrocytic activation indicated by upregulation of glial fibrillary acidic protein (GFAP), which was caused by spontaneous or induced Ab deposition in Tg mice, can be monitored in vivo using bioluminescence imaging (BLI). Methods: We generated bigenic mice by crossing the TgAPP23 line (expressing mutant human APP) with mice expressing a luciferase (luc) reporter driven by the Gfap promoter. Tg(APP23:Gfap-luc) mice were intracerebrally inoculated with brain homogenate from aged TgAPP23 mice, Ab purified from Tg mouse brains, or synthetic Ab amyloid, and monitored by BLI. Results: Spontaneous aggregation of Ab in Tg(APP23:Gfap-luc) mice resulted in upregulation of bioluminescence signal after w13 months. Inoculation of two-month-old Tg(APP23:Gfap-luc) mice with brain homogenate from aged TgAPP23 mice resulted in a signal upregulation at w10 months (8 months postinoculation), while purified Ab aggregates resulted in upregulation of the BLI signal as early as 5 months postinoculation. Amyloids generated from synthetic Ab peptide caused a BLI signal upregulation at w8 months postinoculation, despite inoculating higher amounts of Ab peptide than in the purified sample. Conclusions: Using the BLI paradigm, we were able to demonstrate that both brain-derived and synthetic Ab aggregates were sufficient to induce a self-propagating, prion-like cascade of Ab aggregation in the brains of Tg mice. The difference in time for BLI upregulation between brain-derived and synthetic Ab prions suggests that an auxiliary factor that copurifies with Ab in the brain enhances propagation, that the conformations of brain-derived and synthetic Ab aggregates are distinct, or that multiple conformations are present in the synthetic Ab aggregates, only some of which can initiate self-propagation. These results represent a major step towards identifying self-propagating Ab conformations that could be targeted by therapeutic intervention strategies to stop the spread of Ab aggregates in the brains of AD patients.
O3-04-02
HUMAN Ab DIMERS BIND TO PRPC TO ACTIVATE FYN IN ALZHEIMER’S DISEASE
Megan Larson1, Mathew Sherman1, Mario Nuvolone2, Julie Schneider3, David Bennett4, Adriano Aguzzi3, Sylvain Lesne5, 1University of Minnesota, Minneapolis, Minnesota, United States; 2University Hospital of Zurich, Zurich, Switzerland; 3Rush University Medical Center, Rush Alzheimer’s Disesase Center, Chicago, Illinois, United States; 4Rush University Medical Center, Chicago, Illinois, United States; 5University of Minnesota, Institute for Translational Neuroscience, Minneapolis, Minnesota, United States. Background: Amidst controversy, the cellular form of the prion protein PrPc has been proposed to mediate oligomeric Ab-induced deficits. In contrast, there is consistent evidence that the Src kinase Fyn is activated by Ab
Oral Sessions: O3-04: Cellular and Molecular Mechanisms: Amyloid II
dementia are evident. Such a test may also support in drug development by enabling homogenous cohorts in the clinical trials reducing trial size and costs. In a proof of concept (PoC) study we identified a gene expression signature in blood that detected MCI progressing to AD (prodromal AD) in an MCI population. We have now undertaken additional studies to further investigate and develop this gene expression signature. Methods: Blood samples were obtained from the DiaGenic biobank that previously had been collected from DiaGenic’s multi-center blood collection studies in EU and the US. Total RNA was isolated from blood sampled in PAXgene“¢ tubes. Gene expression in blood was investigated using RT-qPCR on ViiA7 Dx (Life Technologies) for 384 TaqMan assays (384-assay cards) resulting in a quality approved dataset. Data modelling and analysis were performed using multivariate statistical methods. Results: In the previous PoC study we developed the first blood based prodromal AD gene expression biomarker based on an algorithm (model) using the gene expression information from 20 assays to predict MCI progressing to AD in an MCI population. The prediction accuracy of detecting prodromal AD was 74%, sensitivity 74% and specificity 75%. Now we present new results from additional studies on developing and evaluating this gene expression signature for prodromal AD. Conclusions: We have demonstrated that it is possible to detect individuals with MCI progressing to AD (prodromal AD) within 2 years from AD diagnosis based on analysis of gene expression in blood. The new results will increase our understanding of the utility of this potential diagnostic biomarker for prodromal AD. O3-03-06
COMPARISON OF BRIEF COGNITIVE TESTS AND CSF ANALYSIS IN PREDICTING ALZHEIMER’S DISEASE IN MILD COGNITIVE IMPAIRMENT: SIX-YEAR FOLLOW-UP STUDY
Sebastian Palmqvist1, Joakim Hertze1, Lennart Minthon1, Carina Wattmo1, Kaj Blennow2, Henrik Zetterberg2, Elisabet Londos1, Oskar Hansson3, 1Clinical Memory Research Unit, Lund University, Malm€o, Sweden; 2Clinical Neurochemistry Lab, Department of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, M€olndal, Sweden; 3Lund University, Malm€o, Sweden. Background: Early identification of Alzheimer’s disease (AD) is needed both for clinical trials and in clinical practice. In this study, we compared brief cognitive tests and cerebrospinal fluid (CSF) biomarkers in predicting conversion from mild cognitive impairment (MCI) to AD. Methods: At a memory clinic, 133 patients with MCI were followed until development of dementia or until they had been stable over a mean period of 5.9 years (range 3.2-8.8 years). The Mini-Mental State Examination (MMSE), the clock drawing test, total tau, tau phosphorylated at Thr181 (P-tau) and amyloid-b1-42 (Ab42) were assessed at baseline. Results: During clinical follow-up, 47% remained cognitively stable and 53% developed dementia, with an incidence of 13.8%/year. In the group that developed dementia, the prevalence of AD was 73.2% and the other dementias consisted mostly of vascular dementia. When predicting subsequent development of AD among patients with MCI, the cognitive tests classified 81% of the cases correctly (AUC, 0.85; 95% CI, 0.77-0.90) and CSF biomarkers 83% (AUC, 0.89; 95% CI, 0.82-0.94). The combination of cognitive tests and CSF biomarkers (AUC, 0.93; 95% CI 0.87 to 0.96) was significantly better than the cognitive tests (p¼0.01) and the CSF biomarkers (p¼0.04) alone when predicting AD. Conclusions: The MMSE and the clock drawing test were as accurate as CSF biomarkers in predicting future development of AD in patients with MCI. Combining both instruments provided significantly greater accuracy than cognitive tests or CSF biomarkers alone in predicting AD. ORAL SESSIONS: O3-04 CELLULAR AND MOLECULAR MECHANISMS: AMYLOID II O3-04-01
BRAIN-DERIVED AND SYNTHETIC Ab AGGREGATES ARE PRIONS
Jan Stoehr1, Joel Watts1, Zachary Mensinger1, Abby Oehler2, Sunny Grillo1, Stephen DeArmond2, Stanley Prusiner1, Kurt Giles3, 1Institute for
Neurodegenerative Diseases, UCSF, San Francisco, California, United States; 2Department of Pathology, UCSF, San Francisco, California, United States; 3UCSF, San Francisco, California, United States. Background: Aggregation of Ab in the brain is an early event in Alzheimer’s disease (AD), and therefore an ideal target for therapeutic intervention. This aggregation can be induced in susceptible transgenic (Tg) mice by inoculation with brain homogenate containing pre-formed Ab aggregates, suggesting that Ab aggregates are capable of self-propagation in a prionlike manner. We have recently shown that astrocytic activation indicated by upregulation of glial fibrillary acidic protein (GFAP), which was caused by spontaneous or induced Ab deposition in Tg mice, can be monitored in vivo using bioluminescence imaging (BLI). Methods: We generated bigenic mice by crossing the TgAPP23 line (expressing mutant human APP) with mice expressing a luciferase (luc) reporter driven by the Gfap promoter. Tg(APP23:Gfap-luc) mice were intracerebrally inoculated with brain homogenate from aged TgAPP23 mice, Ab purified from Tg mouse brains, or synthetic Ab amyloid, and monitored by BLI. Results: Spontaneous aggregation of Ab in Tg(APP23:Gfap-luc) mice resulted in upregulation of bioluminescence signal after w13 months. Inoculation of two-month-old Tg(APP23:Gfap-luc) mice with brain homogenate from aged TgAPP23 mice resulted in a signal upregulation at w10 months (8 months postinoculation), while purified Ab aggregates resulted in upregulation of the BLI signal as early as 5 months postinoculation. Amyloids generated from synthetic Ab peptide caused a BLI signal upregulation at w8 months postinoculation, despite inoculating higher amounts of Ab peptide than in the purified sample. Conclusions: Using the BLI paradigm, we were able to demonstrate that both brain-derived and synthetic Ab aggregates were sufficient to induce a self-propagating, prion-like cascade of Ab aggregation in the brains of Tg mice. The difference in time for BLI upregulation between brain-derived and synthetic Ab prions suggests that an auxiliary factor that copurifies with Ab in the brain enhances propagation, that the conformations of brain-derived and synthetic Ab aggregates are distinct, or that multiple conformations are present in the synthetic Ab aggregates, only some of which can initiate self-propagation. These results represent a major step towards identifying self-propagating Ab conformations that could be targeted by therapeutic intervention strategies to stop the spread of Ab aggregates in the brains of AD patients.
O3-04-02
HUMAN Ab DIMERS BIND TO PRPC TO ACTIVATE FYN IN ALZHEIMER’S DISEASE
Megan Larson1, Mathew Sherman1, Mario Nuvolone2, Julie Schneider3, David Bennett4, Adriano Aguzzi3, Sylvain Lesne5, 1University of Minnesota, Minneapolis, Minnesota, United States; 2University Hospital of Zurich, Zurich, Switzerland; 3Rush University Medical Center, Rush Alzheimer’s Disesase Center, Chicago, Illinois, United States; 4Rush University Medical Center, Chicago, Illinois, United States; 5University of Minnesota, Institute for Translational Neuroscience, Minneapolis, Minnesota, United States. Background: Amidst controversy, the cellular form of the prion protein PrPc has been proposed to mediate oligomeric Ab-induced deficits. In contrast, there is consistent evidence that the Src kinase Fyn is activated by Ab