- Email: [email protected]
BIOLOGICAL ACTIONS OF TREM2 IN ALZHEIMER'S DISEASE
Podium Presentations: Thursday, July 20, 2017
Study recently funded by the European Commission. Methods: We will focus on literature in cognitively normal, mild cognitive impairment and AD populations that assessed the relationships between several lifestyle measures and AD neuroimaging markers (grey matter volume, glucose metabolism and amyloid deposition). Results: Intellectual enrichment, physical activity, and sleep quality measures have all been shown to be associated with AD biomarkers. Results varied across populations depending on clinical stages, the presence of risk factors (education level or APOE4-carriers) and the specific lifestyle measure and life period. This variation might notably reflect a differential involvement of neuroprotective versus compensatory mechanisms. We will present the Medit-ageing / Silver-Sante Study as an illustration of translational efforts to use lifestyle modification as a disease risk modifier in preclinical population. This research project proposes 18-month training programmes (English learning or meditation training) as well as a passive control in 130 older participants with AD risk factors. The effects will be assessed on neuroimaging markers as well as blood markers, cognition and sleep measures. This project is also designed to improve our understanding of the intervention mechanisms. Conclusions: Our knowledge on the lifestyle factors that impact AD neuroimaging biomarkers along with possible mechanisms and target populations has improved over the last decade. Although observational studies can further refine our understanding of the mechanisms, time has come to translate our knowledge to training programmes that might prevent or delay brain and cognitive changes leading to Alzheimer’s dementia. F5-02-04
CAN COGNITIVE TRAINING BE USED AS A TOOL TO PROMOTE COGNITIVE RESERVE IN OLDER ADULTS? MEASURING SIMILARITIES AND INTERACTION EFFECTS
Sylvie Belleville1,2, Benjamin Boller3,4, Gabriel Ducharme-Laliberte3,4, Samira Mellah5, 1Universite de Montreal, Montreal, QC, Canada; 2Institut Universitaire de Geriatrie de Montreal, Montreal, QC, Canada; 3Institut Universitaire de Geriatrie de Montreal, Montreal, QC, Canada; 4Universite de Montreal, Montreal, QC, Canada; 5Institut Universitaire de Geriatrie de Montreal, Montreal, QC, Canada. Contact e-mail: sylvie.belleville@ umontreal.ca Background: The concept of cognitive reserve has been proposed to account for inter-individual differences in the degree to which brain damage impacts cognition. Cognitive reserve has been associated with early life (e.g., education) and lifelong (e.g., hobbies or profession) cognitive stimulation. Cognitive training may be used as an opportunity to provide or increase cognitive reserve later in life. Hence, an important issue is to determine whether cognitive training has similar effects on the brain and whether persons with low reserve can benefit from these interventions. Methods: In this presentation, we will assess the pattern of task-related brain activation associated with differences in levels of cognitive reserve proxies in older adults. We will then measure the effect of cognitive training on functional brain changes and assess their similarities with those related to reserve proxies. Third, we will evaluate whether the brain and cognitive effects of cognitive training are moderated by differences in reserve proxies (i.e., high vs. low education). Results: Results indicate that reserve proxies and cognitive training act through similar brain mechanisms. Individuals with low reserve benefit highly from cognitive training when training modal-
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ities are adapted to their capacity and show larger post-training activation increase than those with higher reserve. Conclusions: Our results suggest that reserve can be built later in life using appropriate intervention procedures. The findings will be related to the INTERACTIVE model, which proposes that individual characteristics and training format determine the pattern of training-related brain changes. THURSDAY, JULY 20, 2017 FEATURED RESEARCH SESSION F5-03 IMMUNITY AND ALZHEIMER’S DISEASE: BIOLOGICAL MECHANISMS UNDERLYING GENETIC RISK
F5-03-01
BIOLOGICAL ACTIONS OF TREM2 IN ALZHEIMER’S DISEASE
Christian Haass, German Center for Neurodegenerative Diseases (DZNE), Ludwig-Maximilians-University Munich, Munich, Germany. Contact e-mail: [email protected] Background: Sequence variations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to an increased risk for neurodegenerative disorders such as Alzheimer’s disease and frontotemporal lobar degeneration. In brain, TREM2 is predominantly expressed in microglia. Several diseaseassociated TREM2 variants result in a loss-of-function by reducing microglial phagocytosis, impairing lipid sensing, preventing binding of lipoproteins, and affecting shielding of amyloid plaques. Since this suggests that TREM2 deficiency impairs the transition from a resting stage to an activated motile stage, we investigated the consequences of a TREM2 loss-of-function on the mRNA signature of microglia and on brain function in a mouse model expressing the CRISPR/Cas9 introduced T66M mutation. Methods: Microglia were analyzed for changes in their transcriptional profile using Nano String based chips containing 482 microglia-enriched genes. The T66M mutation was introduced by genome editing into the mouse genome using CRISPR/Cas9 editing. Results: In the absence of TREM2, the microglial mRNA signature was shifted towards a resting (i.e. homeostatic) state suggesting that microglia might not be capable of mounting an appropriate response to neuronal injury. Consistent with such a “locked-in” resting state, we found that gene clusters conducive to chemotactic motility were dysregulated. Functional analyses confirmed that a loss of TREM2 impairs appropriate microglial responses to injury and signals that normally evoke chemotaxis. In the TREM2 T66M mouse model we find impaired maturation of mutant Trem2 resulting in an almost complete reduction of soluble Trem2 similar to humans carrying a homozygous p.T66M mutation. Consequently, macrophages derived from Trem2 p.T66M knock-in mice display significantly reduced phagocytic activity and delayed resolution of inflammation upon lipopolysaccharide stimulation. Immunohistochemistry together with in vivo TSPO small animal positron emission tomography (mPET) demonstrated an age-dependent reduction of microglial activity. Conclusions: Our transcriptomic analyses of microglia with and without TERM2 indicate that microglia might be locked in a homeostatic stage when TREM2 is absent. This may prevent microglia from actively responding to neuronal injury. Moreover, a TREM2 loss-of-function mutation causes systemic metabolic alterations throughout the brain.
Study recently funded by the European Commission. Methods: We will focus on literature in cognitively normal, mild cognitive impairment and AD populations that assessed the relationships between several lifestyle measures and AD neuroimaging markers (grey matter volume, glucose metabolism and amyloid deposition). Results: Intellectual enrichment, physical activity, and sleep quality measures have all been shown to be associated with AD biomarkers. Results varied across populations depending on clinical stages, the presence of risk factors (education level or APOE4-carriers) and the specific lifestyle measure and life period. This variation might notably reflect a differential involvement of neuroprotective versus compensatory mechanisms. We will present the Medit-ageing / Silver-Sante Study as an illustration of translational efforts to use lifestyle modification as a disease risk modifier in preclinical population. This research project proposes 18-month training programmes (English learning or meditation training) as well as a passive control in 130 older participants with AD risk factors. The effects will be assessed on neuroimaging markers as well as blood markers, cognition and sleep measures. This project is also designed to improve our understanding of the intervention mechanisms. Conclusions: Our knowledge on the lifestyle factors that impact AD neuroimaging biomarkers along with possible mechanisms and target populations has improved over the last decade. Although observational studies can further refine our understanding of the mechanisms, time has come to translate our knowledge to training programmes that might prevent or delay brain and cognitive changes leading to Alzheimer’s dementia. F5-02-04
CAN COGNITIVE TRAINING BE USED AS A TOOL TO PROMOTE COGNITIVE RESERVE IN OLDER ADULTS? MEASURING SIMILARITIES AND INTERACTION EFFECTS
Sylvie Belleville1,2, Benjamin Boller3,4, Gabriel Ducharme-Laliberte3,4, Samira Mellah5, 1Universite de Montreal, Montreal, QC, Canada; 2Institut Universitaire de Geriatrie de Montreal, Montreal, QC, Canada; 3Institut Universitaire de Geriatrie de Montreal, Montreal, QC, Canada; 4Universite de Montreal, Montreal, QC, Canada; 5Institut Universitaire de Geriatrie de Montreal, Montreal, QC, Canada. Contact e-mail: sylvie.belleville@ umontreal.ca Background: The concept of cognitive reserve has been proposed to account for inter-individual differences in the degree to which brain damage impacts cognition. Cognitive reserve has been associated with early life (e.g., education) and lifelong (e.g., hobbies or profession) cognitive stimulation. Cognitive training may be used as an opportunity to provide or increase cognitive reserve later in life. Hence, an important issue is to determine whether cognitive training has similar effects on the brain and whether persons with low reserve can benefit from these interventions. Methods: In this presentation, we will assess the pattern of task-related brain activation associated with differences in levels of cognitive reserve proxies in older adults. We will then measure the effect of cognitive training on functional brain changes and assess their similarities with those related to reserve proxies. Third, we will evaluate whether the brain and cognitive effects of cognitive training are moderated by differences in reserve proxies (i.e., high vs. low education). Results: Results indicate that reserve proxies and cognitive training act through similar brain mechanisms. Individuals with low reserve benefit highly from cognitive training when training modal-
P1447
ities are adapted to their capacity and show larger post-training activation increase than those with higher reserve. Conclusions: Our results suggest that reserve can be built later in life using appropriate intervention procedures. The findings will be related to the INTERACTIVE model, which proposes that individual characteristics and training format determine the pattern of training-related brain changes. THURSDAY, JULY 20, 2017 FEATURED RESEARCH SESSION F5-03 IMMUNITY AND ALZHEIMER’S DISEASE: BIOLOGICAL MECHANISMS UNDERLYING GENETIC RISK
F5-03-01
BIOLOGICAL ACTIONS OF TREM2 IN ALZHEIMER’S DISEASE
Christian Haass, German Center for Neurodegenerative Diseases (DZNE), Ludwig-Maximilians-University Munich, Munich, Germany. Contact e-mail: [email protected] Background: Sequence variations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to an increased risk for neurodegenerative disorders such as Alzheimer’s disease and frontotemporal lobar degeneration. In brain, TREM2 is predominantly expressed in microglia. Several diseaseassociated TREM2 variants result in a loss-of-function by reducing microglial phagocytosis, impairing lipid sensing, preventing binding of lipoproteins, and affecting shielding of amyloid plaques. Since this suggests that TREM2 deficiency impairs the transition from a resting stage to an activated motile stage, we investigated the consequences of a TREM2 loss-of-function on the mRNA signature of microglia and on brain function in a mouse model expressing the CRISPR/Cas9 introduced T66M mutation. Methods: Microglia were analyzed for changes in their transcriptional profile using Nano String based chips containing 482 microglia-enriched genes. The T66M mutation was introduced by genome editing into the mouse genome using CRISPR/Cas9 editing. Results: In the absence of TREM2, the microglial mRNA signature was shifted towards a resting (i.e. homeostatic) state suggesting that microglia might not be capable of mounting an appropriate response to neuronal injury. Consistent with such a “locked-in” resting state, we found that gene clusters conducive to chemotactic motility were dysregulated. Functional analyses confirmed that a loss of TREM2 impairs appropriate microglial responses to injury and signals that normally evoke chemotaxis. In the TREM2 T66M mouse model we find impaired maturation of mutant Trem2 resulting in an almost complete reduction of soluble Trem2 similar to humans carrying a homozygous p.T66M mutation. Consequently, macrophages derived from Trem2 p.T66M knock-in mice display significantly reduced phagocytic activity and delayed resolution of inflammation upon lipopolysaccharide stimulation. Immunohistochemistry together with in vivo TSPO small animal positron emission tomography (mPET) demonstrated an age-dependent reduction of microglial activity. Conclusions: Our transcriptomic analyses of microglia with and without TERM2 indicate that microglia might be locked in a homeostatic stage when TREM2 is absent. This may prevent microglia from actively responding to neuronal injury. Moreover, a TREM2 loss-of-function mutation causes systemic metabolic alterations throughout the brain.