- Email: [email protected]
ABETA PLAQUE-ASSOCIATED MICROGLIA PRIMING IN ALZHEIMER'S DISEASE
P462
Poster Presentations: Sunday, July 24, 2016
after birth, for up to 8 weeks, then prepared for analysis for both metabolites and signalling pathways associated with mitochondria function. Results: The temporal metabolic profile of brains harvested from 5XFAD mice was significantly different from the metabolic profile of brains harvested from control mice. Expression of metabolic enzymes was reflective of metabolic changes. Signalling pathways associated with mitochondria function were altered in brains of 5XFAD mice compared with control mice. Conclusions: Temporal alterations in brain energy metabolism were found in 5XFAD mice compared to control mice.
P1-155
POST-MORTEM BRAIN TISSUE CHARACTERISATION OF INFLAMMATORY AND PATHOLOGICAL HALLMARKS OF ALZHEIMER’S DISEASE DURING DISEASE PROGRESSION
Martina M. Hughes1, Beatriz G. Perez-Nievas1, Claire Troakes1,2, Michael Perkinton3, Diane P. Hanger1, Wendy Noble1, 1Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, United Kingdom; 2King’s College London, MRC London Neurodegenerative Diseases Brain Bank, London, United Kingdom; 3MedImmune Limited, Cambridge, United Kingdom. Contact e-mail: [email protected] Background: Accumulations of activated astrocytes and phos-
P1-154
P66SHC EXPRESSION AFFECTS THE METABOLIC STATE AND AMYLOID-b SENSITIVITY IN NEURONAL CELLS
Asad Lone, Robert C. Cumming, University of Western Ontario, London, ON, Canada. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is characterized by the
accumulation of extracellular amyloid beta (Ab) peptide within plaques, a factor believed to play a major role in AD pathogenesis. Ab deposition is frequently accompanied by extensive neuronal death and synaptic loss in the AD brain. However, approximately 40% of the elderly may accumulate significant Ab containing plaques within their brains, yet show no symptoms of dementia. These observations suggest that some neurons within the brains of elderly individuals are resistant to Ab toxicity. We recently demonstrated that neuronal cells lines selected for resistance to Ab toxicity exhibit a change in their metabolism; shifting away from mitochondrial dependent oxidative phosphorylation (OXPHOS), and instead rely on aerobic glycolysis for their energy needs. The adaptor protein p66SHC has been shown to play a role in aging, regulation of redox balance and response to oxidative stress. Recent studies revealed that loss of p66SHC expression results in a shift in metabolic activity from mitochondrial OXPHOS to cytosolic aerobic glycolysis. We therefore hypothesized that p66SHC expression affects the metabolic state and Ab sensitivity in rodent neuronal cell lines. Methods: We transiently overexpressed p66SHC in HT22 cells, a mouse hippocampal cell line with low endogenous p66SHC expression, and knocked down endogenous p66SHC in B12 cells, a rat neuronal precursor cell line which expresses high levels of p66SHC. Changes in metabolism, ROS levels and mitochondrial membrane potential were measured. Furthermore, we examined the subcellular localization of the phosphorylated and activated form of p66SHC. Lastly, we investigated if p66SHCexpression and activation increased Ab sensitivity in both cell lines in an OXPHOS dependent manner. Results: Transient overexpression of p66SHC repressed glycolysis and promoted mitochondrial OXPHOS, with a concurrent depolarization of mitochondrial membrane potential and increase in ROS levels. The opposite effect was observed when endogenous p66SHC expression was knocked down. The phosphorylated and activated form of p66SHC was found to localize to mitochondria. Elevated expression and activation of p66SHC rendered both cell lines more sensitive to Ab toxicity. Conclusions: Expression and activation of p66SHC renders CNS cells more sensitive to Ab toxicity by promoting mitochondrial OXPHOS while repressing aerobic glycolysis.
phorylated oligomeric tau in synapses are key pathological correlates of cognitive decline in Alzheimer’s disease (AD) (Serrano-Pozo et al., 2011, Perez-Nievas et al., 2013). Additionally, P2X7 receptor (R) expression is increased in neurodegenerative disorders, while inflammatory factors secreted from activated astrocytes influence tau phosphorylation, cleavage and function (Skaper et al., 2010, Garwood et al., 2011). Thus, amyloid beta induced astrocytic P2X7R activation may modulate disease-related changes in tau and synaptic function via an inflammatory pathway. Therefore, we sought to characterise the temporal association of astrocyte activation with tau mislocalisation to synapses, P2X7R amounts and localisation and synaptic integrity in post-mortem brain tissue from controls and Braak stages I-VI. Methods: Frozen post-mortem human frontal cortex from control (n¼4) and pathologically confirmed cases of sporadic AD, Braak stage I and II (n¼8), III and IV (n¼10), V and VI (n¼10), were obtained from the MRC London Neurodegenerative Diseases Brain Bank. Biochemical assessment of target protein of interest was carried out on total brain homogenates and synaptic and cytosolic fractions. Results: Elevated levels of total tau (tTau), phosphorylated tau (pTau) and GFAP were observed in Braak stage III-VI tissues relative to controls. Significant disease associated increases in tTau and pTau levels were observed in the synapse, while cytosolic GFAP levels in Braak stage III-IV were robustly elevated compared with controls. P2X7R protein amounts positively correlated with changes in APoE protein in the total homogenate, while a loss of synaptic P2X7R levels in Braak stage V-VI negatively correlated with synaptic APoE amounts. Conclusions: These data support the idea that soluble pTau species mislocalise and accumulate in the synapse in late stage AD. In addition, astrocytic phenotype appears to be altered during disease progression. These data further support a potential role for inflammatory astrocytes in mediating the progression of AD. Tissue was provided by the London Neurodegenerative Diseases Brain Bank, which receives funding from the MRC and from the Alzheimer’s Society and ARUK (through the Brains for Dementia Research project).
P1-156
ABETA PLAQUE-ASSOCIATED MICROGLIA PRIMING IN ALZHEIMER’S DISEASE
Zhuoran Yin1,2, Divya Raj3, Nasrin Saiepour4, Debby Van Dam5,6, Nieske Brouwer3, Inge Holtman3, Bart Eggen3, Uwe-Karsten Hanisch4, Elly Hol7, Willem Kamphuis7, Thomas Bayer8, Peter Paul de Deyn9,10, Erik Boddeke3, 1University Medical Center Groningen, Goningen, Netherlands; 2Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China; 3University Medical Center Groningen, Groningen, Netherlands; 4University Medicine Gottingen, Gottingen,
Poster Presentations: Sunday, July 24, 2016 Germany; 5University of Antwerp, Antwerp, Belgium; 6Institute Born-Bunge, Antwerp, Belgium; 7Netherlands Institute for Neuroscience, Utrecht, Netherlands; 8University Goettingen, Goettingen, Germany; 9 University of Groningen, University Medical Center Groningen (UMCG), Department of Neurology and Alzheimer Research Center, Groningen, Netherlands; 10Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Contact e-mail: [email protected] Background: The pathogenesis of Alzheimer’s disease (AD), characterized by accumulation of extracellular amyloid beta (Abeta) plaques within the brain, is associated with profound microglia activation around the plaques. Furthermore, aging of the brain has been associated with enhanced sensitivity of microglia to proinflammatory stimuli, so-called microglia priming. In this study, we investigated to which extent microglia priming is associated with Abeta plaque pathology. Methods: We measured the expression of markers for microglia priming in three established mouse models for AD, i.e. APP23, APPPS1 and 5XFAD mice, as well as in human AD brain. Results: Expression of specific protein markers for microglia priming, Mac-2 and MHC II, was observed in Abeta plaque-associated microglia in 16and 20-month-old APP23 mice, 18-month-old APPPS1 mice and 12-month-old 5XFAD mice, but not in microglia outside the plaque areas nor in microglia of age-matched wild-type (WT) mice. After i.p. injection of LPS, the expression of Mac2 and MHC II was enhanced in APP23 mice and the expression of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) was enhanced specifically in plaque-associated microglia in 20-month-old APP23 mice and 12-month-old 5XFAD mice. In contrast, microglia outside the plaque areas showed only moderate expression of IL-1beta in response to LPS, comparable to what was observed in wild-type mice. In the cortex of old (24 months) wild-type mice, specific markers for microglia priming were detected sporadically. Gene expression profile of Abeta plaque-associated microglia (MHC II+ microglia) in 9-monthold 5XFAD mice also revealed the primed phenotype. In early-onset familial AD (EOFAD), expression of priming markers, HLA-DR (MHC II), Apoe and Axl, was specifically higher in mature plaque regions, compared to non-plaque regions. Conclusions: In transgenic AD mouse models, APP23 mice, APPPS1 mice and 5XFAD mice, microglia priming is confined to the Abeta plaque areas at early age, and later on occurs in tandem with aging-associated priming. In EOFAD patients but not in late-onset AD (LOAD), microglia priming occurred in the vicinity of Abeta plaques.
P1-157
INCREASED TLR8 AND 9 EXPRESSION CORRELATES WITH PRESERVED HYPPOCAMPAL VOLUMES AND LACK OF PROGRESSION TO ALZHEIMER’S DISEASE IN INDIVIDUALS WITH A DIAGNOSIS OF MILD COGNITIVE IMPAIRMENT
Francesca La Rosa1, Marina Saresella2, Federica Piancone3, Ivana Marventano3, Elena Calabrese4, Raffaello Nemni4,5, Mario Clerici4,5, 1 Foundation Don C Gnocchi, Milano, Italy; 2Foundation don C Gnocchi, Milano, Italy; 3Foundation don C Gnocchi, Milano, Italy; 4IRCCS Don Carlo Gnocchi Foundation - ONLUS, Milan, Italy; 5University of Milan, Milan, Italy. Contact e-mail: [email protected]
P463
Background: Mild cognitive impairment (MCI) is widely accepted as an intermediate state between the lack of pathologic cognitive impairment and Alzheimer’s disease (AD). Only a percentage of MCI individuals, nevertheless, progresses to AD. Amyloid theory, alterations of the blood-brain barrier and neuroinflammation seem to play an important role in AD neurodegeneration; pathogens infection, and in particular herpes simplex virus (HSV) infection, is also suggested to be involved in the pathogenesis of AD. The innate immune response to pathogens is triggered by the ligation of toll like receptors (TLR) on the surface of cells. We recently described that TLR expression is significantly upregulated in MCI compared to AD individuals, suggesting that the ability of MCI individual to mount stronger innate immune responses against pathogens is impaired in AD. We examined TLR expression and cytokine production in 46 individuals with a diagnosis of MCI who did (progressors) or did not (non progressors) progress to AD over a 24 months’ time period. Methods: TLRs expression (upon TLRs agonists-stimulation) and cytokine production (upon Ab1-42 stimulation) was measured at baseline in CD14+ immune cells of 46 MCI individuals who did (N¼25) or did not (N¼2) progress to AD using Flow Cytometry. ApoE4 status and hippocampus left and right volumes (using NMR tecniques) were analyzed as well in all individuals. Results: Results of analysed performed at baseline, when all individuals were clinically classified as MCI, in non-progressors compared to progressors: 1) TLR8 and TLR9 expression on CD14+ cells was significantly upregulated (p¼ 0.0008 and 0.05 respectively); 2) Ab-stimulated production of the pro-inflammatory cytokines IL-6, TNFa, IL-1b by CD14+ cells was significantly reduced (p<0.05); and 3) left and right hyppocampal volumes were better preserved (p<0.05). No differences were detected in the ApoE4 status. Conclusions: The expression of TLR8 and TLR9, two receptors that activated by viral replication byproducts, is significantly increased in MCI individuals who do not progress to AD. This correlates with better preserved hyppocampal volumes, suggesting that the ability to mount stronger antiviral responses is associated with protection against AD. The reduced production of proinflammatory cytokines is in apparent contrast with TLR results and needs to be further analyzed.
P1-158
THE ADAPTIVE IMMUNE SYSTEM CRITICALLY REGULATES ALZHEIMER’S DISEASE PATHOGENESIS BY MODULATING MICROGLIAL FUNCTION
Samuel E. Marsh1, Alborz Karimzadeh1, Edsel M. Abud1, Anita Lakatos1, Stephen T. Yeung2, Hayk Davtyan3, Gianna Fote1, Lydia Lau1, Jason G. Weinger4, Thomas E. Lane5, Wayne W. Poon1, Matthew A. Inlay1, Mathew Blurton-Jones1, 1University of California, Irvine, Irvine, CA, USA; 2 University of Connecticut, Farmington, CT, USA; 3Institute for Molecular Medicine, Huntington Beach, CA, USA; 4Neurocentria, Fremont, CA, USA; 5 University of Utah School of Medicine, Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: The innate immune system is strongly implicated in Alzheimer’s disease (AD) pathogenesis. In contrast, very few studies have examined the potential role of the adaptive immune response in this disorder. The extensive testing and clinical
Poster Presentations: Sunday, July 24, 2016
after birth, for up to 8 weeks, then prepared for analysis for both metabolites and signalling pathways associated with mitochondria function. Results: The temporal metabolic profile of brains harvested from 5XFAD mice was significantly different from the metabolic profile of brains harvested from control mice. Expression of metabolic enzymes was reflective of metabolic changes. Signalling pathways associated with mitochondria function were altered in brains of 5XFAD mice compared with control mice. Conclusions: Temporal alterations in brain energy metabolism were found in 5XFAD mice compared to control mice.
P1-155
POST-MORTEM BRAIN TISSUE CHARACTERISATION OF INFLAMMATORY AND PATHOLOGICAL HALLMARKS OF ALZHEIMER’S DISEASE DURING DISEASE PROGRESSION
Martina M. Hughes1, Beatriz G. Perez-Nievas1, Claire Troakes1,2, Michael Perkinton3, Diane P. Hanger1, Wendy Noble1, 1Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, United Kingdom; 2King’s College London, MRC London Neurodegenerative Diseases Brain Bank, London, United Kingdom; 3MedImmune Limited, Cambridge, United Kingdom. Contact e-mail: [email protected] Background: Accumulations of activated astrocytes and phos-
P1-154
P66SHC EXPRESSION AFFECTS THE METABOLIC STATE AND AMYLOID-b SENSITIVITY IN NEURONAL CELLS
Asad Lone, Robert C. Cumming, University of Western Ontario, London, ON, Canada. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is characterized by the
accumulation of extracellular amyloid beta (Ab) peptide within plaques, a factor believed to play a major role in AD pathogenesis. Ab deposition is frequently accompanied by extensive neuronal death and synaptic loss in the AD brain. However, approximately 40% of the elderly may accumulate significant Ab containing plaques within their brains, yet show no symptoms of dementia. These observations suggest that some neurons within the brains of elderly individuals are resistant to Ab toxicity. We recently demonstrated that neuronal cells lines selected for resistance to Ab toxicity exhibit a change in their metabolism; shifting away from mitochondrial dependent oxidative phosphorylation (OXPHOS), and instead rely on aerobic glycolysis for their energy needs. The adaptor protein p66SHC has been shown to play a role in aging, regulation of redox balance and response to oxidative stress. Recent studies revealed that loss of p66SHC expression results in a shift in metabolic activity from mitochondrial OXPHOS to cytosolic aerobic glycolysis. We therefore hypothesized that p66SHC expression affects the metabolic state and Ab sensitivity in rodent neuronal cell lines. Methods: We transiently overexpressed p66SHC in HT22 cells, a mouse hippocampal cell line with low endogenous p66SHC expression, and knocked down endogenous p66SHC in B12 cells, a rat neuronal precursor cell line which expresses high levels of p66SHC. Changes in metabolism, ROS levels and mitochondrial membrane potential were measured. Furthermore, we examined the subcellular localization of the phosphorylated and activated form of p66SHC. Lastly, we investigated if p66SHCexpression and activation increased Ab sensitivity in both cell lines in an OXPHOS dependent manner. Results: Transient overexpression of p66SHC repressed glycolysis and promoted mitochondrial OXPHOS, with a concurrent depolarization of mitochondrial membrane potential and increase in ROS levels. The opposite effect was observed when endogenous p66SHC expression was knocked down. The phosphorylated and activated form of p66SHC was found to localize to mitochondria. Elevated expression and activation of p66SHC rendered both cell lines more sensitive to Ab toxicity. Conclusions: Expression and activation of p66SHC renders CNS cells more sensitive to Ab toxicity by promoting mitochondrial OXPHOS while repressing aerobic glycolysis.
phorylated oligomeric tau in synapses are key pathological correlates of cognitive decline in Alzheimer’s disease (AD) (Serrano-Pozo et al., 2011, Perez-Nievas et al., 2013). Additionally, P2X7 receptor (R) expression is increased in neurodegenerative disorders, while inflammatory factors secreted from activated astrocytes influence tau phosphorylation, cleavage and function (Skaper et al., 2010, Garwood et al., 2011). Thus, amyloid beta induced astrocytic P2X7R activation may modulate disease-related changes in tau and synaptic function via an inflammatory pathway. Therefore, we sought to characterise the temporal association of astrocyte activation with tau mislocalisation to synapses, P2X7R amounts and localisation and synaptic integrity in post-mortem brain tissue from controls and Braak stages I-VI. Methods: Frozen post-mortem human frontal cortex from control (n¼4) and pathologically confirmed cases of sporadic AD, Braak stage I and II (n¼8), III and IV (n¼10), V and VI (n¼10), were obtained from the MRC London Neurodegenerative Diseases Brain Bank. Biochemical assessment of target protein of interest was carried out on total brain homogenates and synaptic and cytosolic fractions. Results: Elevated levels of total tau (tTau), phosphorylated tau (pTau) and GFAP were observed in Braak stage III-VI tissues relative to controls. Significant disease associated increases in tTau and pTau levels were observed in the synapse, while cytosolic GFAP levels in Braak stage III-IV were robustly elevated compared with controls. P2X7R protein amounts positively correlated with changes in APoE protein in the total homogenate, while a loss of synaptic P2X7R levels in Braak stage V-VI negatively correlated with synaptic APoE amounts. Conclusions: These data support the idea that soluble pTau species mislocalise and accumulate in the synapse in late stage AD. In addition, astrocytic phenotype appears to be altered during disease progression. These data further support a potential role for inflammatory astrocytes in mediating the progression of AD. Tissue was provided by the London Neurodegenerative Diseases Brain Bank, which receives funding from the MRC and from the Alzheimer’s Society and ARUK (through the Brains for Dementia Research project).
P1-156
ABETA PLAQUE-ASSOCIATED MICROGLIA PRIMING IN ALZHEIMER’S DISEASE
Zhuoran Yin1,2, Divya Raj3, Nasrin Saiepour4, Debby Van Dam5,6, Nieske Brouwer3, Inge Holtman3, Bart Eggen3, Uwe-Karsten Hanisch4, Elly Hol7, Willem Kamphuis7, Thomas Bayer8, Peter Paul de Deyn9,10, Erik Boddeke3, 1University Medical Center Groningen, Goningen, Netherlands; 2Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China; 3University Medical Center Groningen, Groningen, Netherlands; 4University Medicine Gottingen, Gottingen,
Poster Presentations: Sunday, July 24, 2016 Germany; 5University of Antwerp, Antwerp, Belgium; 6Institute Born-Bunge, Antwerp, Belgium; 7Netherlands Institute for Neuroscience, Utrecht, Netherlands; 8University Goettingen, Goettingen, Germany; 9 University of Groningen, University Medical Center Groningen (UMCG), Department of Neurology and Alzheimer Research Center, Groningen, Netherlands; 10Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Contact e-mail: [email protected] Background: The pathogenesis of Alzheimer’s disease (AD), characterized by accumulation of extracellular amyloid beta (Abeta) plaques within the brain, is associated with profound microglia activation around the plaques. Furthermore, aging of the brain has been associated with enhanced sensitivity of microglia to proinflammatory stimuli, so-called microglia priming. In this study, we investigated to which extent microglia priming is associated with Abeta plaque pathology. Methods: We measured the expression of markers for microglia priming in three established mouse models for AD, i.e. APP23, APPPS1 and 5XFAD mice, as well as in human AD brain. Results: Expression of specific protein markers for microglia priming, Mac-2 and MHC II, was observed in Abeta plaque-associated microglia in 16and 20-month-old APP23 mice, 18-month-old APPPS1 mice and 12-month-old 5XFAD mice, but not in microglia outside the plaque areas nor in microglia of age-matched wild-type (WT) mice. After i.p. injection of LPS, the expression of Mac2 and MHC II was enhanced in APP23 mice and the expression of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) was enhanced specifically in plaque-associated microglia in 20-month-old APP23 mice and 12-month-old 5XFAD mice. In contrast, microglia outside the plaque areas showed only moderate expression of IL-1beta in response to LPS, comparable to what was observed in wild-type mice. In the cortex of old (24 months) wild-type mice, specific markers for microglia priming were detected sporadically. Gene expression profile of Abeta plaque-associated microglia (MHC II+ microglia) in 9-monthold 5XFAD mice also revealed the primed phenotype. In early-onset familial AD (EOFAD), expression of priming markers, HLA-DR (MHC II), Apoe and Axl, was specifically higher in mature plaque regions, compared to non-plaque regions. Conclusions: In transgenic AD mouse models, APP23 mice, APPPS1 mice and 5XFAD mice, microglia priming is confined to the Abeta plaque areas at early age, and later on occurs in tandem with aging-associated priming. In EOFAD patients but not in late-onset AD (LOAD), microglia priming occurred in the vicinity of Abeta plaques.
P1-157
INCREASED TLR8 AND 9 EXPRESSION CORRELATES WITH PRESERVED HYPPOCAMPAL VOLUMES AND LACK OF PROGRESSION TO ALZHEIMER’S DISEASE IN INDIVIDUALS WITH A DIAGNOSIS OF MILD COGNITIVE IMPAIRMENT
Francesca La Rosa1, Marina Saresella2, Federica Piancone3, Ivana Marventano3, Elena Calabrese4, Raffaello Nemni4,5, Mario Clerici4,5, 1 Foundation Don C Gnocchi, Milano, Italy; 2Foundation don C Gnocchi, Milano, Italy; 3Foundation don C Gnocchi, Milano, Italy; 4IRCCS Don Carlo Gnocchi Foundation - ONLUS, Milan, Italy; 5University of Milan, Milan, Italy. Contact e-mail: [email protected]
P463
Background: Mild cognitive impairment (MCI) is widely accepted as an intermediate state between the lack of pathologic cognitive impairment and Alzheimer’s disease (AD). Only a percentage of MCI individuals, nevertheless, progresses to AD. Amyloid theory, alterations of the blood-brain barrier and neuroinflammation seem to play an important role in AD neurodegeneration; pathogens infection, and in particular herpes simplex virus (HSV) infection, is also suggested to be involved in the pathogenesis of AD. The innate immune response to pathogens is triggered by the ligation of toll like receptors (TLR) on the surface of cells. We recently described that TLR expression is significantly upregulated in MCI compared to AD individuals, suggesting that the ability of MCI individual to mount stronger innate immune responses against pathogens is impaired in AD. We examined TLR expression and cytokine production in 46 individuals with a diagnosis of MCI who did (progressors) or did not (non progressors) progress to AD over a 24 months’ time period. Methods: TLRs expression (upon TLRs agonists-stimulation) and cytokine production (upon Ab1-42 stimulation) was measured at baseline in CD14+ immune cells of 46 MCI individuals who did (N¼25) or did not (N¼2) progress to AD using Flow Cytometry. ApoE4 status and hippocampus left and right volumes (using NMR tecniques) were analyzed as well in all individuals. Results: Results of analysed performed at baseline, when all individuals were clinically classified as MCI, in non-progressors compared to progressors: 1) TLR8 and TLR9 expression on CD14+ cells was significantly upregulated (p¼ 0.0008 and 0.05 respectively); 2) Ab-stimulated production of the pro-inflammatory cytokines IL-6, TNFa, IL-1b by CD14+ cells was significantly reduced (p<0.05); and 3) left and right hyppocampal volumes were better preserved (p<0.05). No differences were detected in the ApoE4 status. Conclusions: The expression of TLR8 and TLR9, two receptors that activated by viral replication byproducts, is significantly increased in MCI individuals who do not progress to AD. This correlates with better preserved hyppocampal volumes, suggesting that the ability to mount stronger antiviral responses is associated with protection against AD. The reduced production of proinflammatory cytokines is in apparent contrast with TLR results and needs to be further analyzed.
P1-158
THE ADAPTIVE IMMUNE SYSTEM CRITICALLY REGULATES ALZHEIMER’S DISEASE PATHOGENESIS BY MODULATING MICROGLIAL FUNCTION
Samuel E. Marsh1, Alborz Karimzadeh1, Edsel M. Abud1, Anita Lakatos1, Stephen T. Yeung2, Hayk Davtyan3, Gianna Fote1, Lydia Lau1, Jason G. Weinger4, Thomas E. Lane5, Wayne W. Poon1, Matthew A. Inlay1, Mathew Blurton-Jones1, 1University of California, Irvine, Irvine, CA, USA; 2 University of Connecticut, Farmington, CT, USA; 3Institute for Molecular Medicine, Huntington Beach, CA, USA; 4Neurocentria, Fremont, CA, USA; 5 University of Utah School of Medicine, Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: The innate immune system is strongly implicated in Alzheimer’s disease (AD) pathogenesis. In contrast, very few studies have examined the potential role of the adaptive immune response in this disorder. The extensive testing and clinical