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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    305—Beta and Gamma Secretase: BACE and Presenilin

    Monday, November 11, 2013, 8:00 am - 11:00 am

    305.03: Presenilin1 mutant-dependent alterations in plasma cytokines and signaling factors following environmental enrichment and the impact on adult hippocampal neurogenesis

    Location: 23A

    ">*K. VEERARAGHAVALU1, D. BERDNIK2, X. ZHANG1, T. WYSS-CORAY2, S. S. SISODIA1;
    1Univ. Chicago, CHICAGO, IL; 2The Dept. of Neurolog. Sci., Stanford Univ., Palo Alto, CA

    Abstract Body: Early-onset familial forms of the Alzheimer’s disease (FAD) are caused by inheritance of mutant genes encoding presenilin 1 (PS1) variants. We reported that ubiquitous expression of human FAD-linked PS1 variants in mice impairs environmental enrichment (EE)-induced adult hippocampal neural progenitor cell (AHNPC) proliferation and neuronal differentiation, and that microglia expressing PS1 variants secrete elevated level of cytokines and soluble factors, including: Eotaxin (CCL11), CXCL1, MIP2, TIMP1, Leptin, IGFBP6, that collectively impair the proliferation and differentiation phenotypes of wild-type AHNPCs in vitro (Choi et al., Neuron 2008). In view of our findings that non-CNS derived, blood-borne cytokines (e.g. Eotaxin) are elevated in the plasma of aging mice and are correlated with suppression of adult hippocampal neurogenesis (Villeda et al., Nature 2011), we sought to examine the profiles of cytokines and other immunomodulatory factors in the plasma from 2- or 6-month old transgenic mice expressing either human wild type PS1 (hPS1WT) or two different PS1 mutants following exposure to standard housing (SH) or EE-housing conditions. The relative concentrations of cytokines and signaling factors were measured using an antibody-based multiplex immunoassay. Preliminary analysis reveals that in comparison to SH animals, exposure of 2 month old hPS1WT mice to EE-conditions resulted in significant changes in the levels of 33 factors out of 403 tested (P < 0.05). For example, the levels of IL16, CCL12, CCL24, MMP9, CX3CL1, LRP4, LIF, FGFs (11, 12, & 13), TNFRSF (21 & 1B), Inhibin β-C chain and Prokineticin 1 were increased by at least 1.5-fold, while the levels of FASLG, FGF21 and IL17B were decreased by at least 1.5-fold. Notably, several of these factors have been positively correlated to neurogenesis in different experimental settings. We will present data that compare the levels of cytokines and signaling factors in the plasma of mice expressing hPS1WT to mice expressing PS1 variants that are exposed to SH and EE conditions. We anticipate that this unbiased multiplex screening approach will uncover factors that play a role in mediating mutant PS1-dependent impairments on EE-induced hippocampal neurogenesis.

    Lay Language Summary: We examined the proliferation status of adult neural progenitors in a mouse model that express human familial Alzheimer’s disease (FAD)-linked Presenilin 1 (PS1) mutants. Our results reveal that ubiquitous expression of PS1 variants in mice impairs environmental enrichment (EE)-induced adult hippocampal neural progenitor cell (AHNPC) proliferation and neuronal differentiation, and that microglia expressing PS1 variants secrete elevated level of cytokines that collectively impair the proliferation/differentiation phenotypes of wild-type AHNPCs in vitro. In view of our findings that non-CNS derived, blood-borne cytokines are elevated in the plasma of aging mice and are correlated with suppression of adult hippocampal neurogenesis, we examined the profiles of cytokines and other immunomodulatory factors in the plasma from transgenic mice expressing either human wild type PS1 (hPS1WT) or two different PS1 mutants following exposure to standard or EE-housing conditions. Our studies uncover factors that have been correlated to neurogenesis in different experimental settings and thus, may play a role in mediating mutant PS1-dependent impairments on EE-induced hippocampal neurogenesis.
    AD is the most common form of dementia characterized by progressive memory loss that seriously interferes with normal thinking, behavior and day-to-day activities. It is the fourth leading cause of death in elderly Americans and has become the strongest emotional burden for families with elderly parents are diagnosed with AD. Currently, there is no cure or a promising treatment strategy in place, which can stop progression of AD or improve memory loss. Considering the rising cost of healthcare, Scientists in around the world have invested efforts towards finding better ways to perform early diagnosis, prevent progression or treat this dreadful disease.
    At a pathological level, AD is characterized by gradual loss of neurons, deterioration of cognitive function, extracellular deposition of β-amyloid (Aβ) peptides and intra neuronal neurofibrillary tangles. Aβ are derived from larger amyloid precursor protein by the action of γ-secretase enzyme. PS1 is the catalytic component of γ-secretase. Intriguingly, a low percentage of diagnosed AD cases result from inheritance of mutations in Presenilin-1 gene, which pre-disposes them to disease symptoms as early as at the age of ~30 years. Understanding the normal functions of PS1 and the mechanisms by which mutated versions of this protein causes AD remains elusive, and is an area of active research for the past decade.
    The molecular mechanism(s) by which expression of mutant PS1 cause FAD are not fully understood, but the widely held view is that mutant PS1 enhances the ratio of Aβ42/Aβ40 peptides, leading to nucleation, oligomerization and neuropathogenicity of Aβ42 peptides. Notwithstanding this important aspect of pathogenesis mediated by FAD-linked PS1 variants, it is increasingly becoming clear that expression of mutant PS1 polypeptides have more global effects on neuronal function and pathophysiology. Of late, a pivotal role for PS1 was demonstrated in the context of neurogenesis that is sustained throughout the adult hood.
    Birth of new neurons take place throughout adult hood in certain specific areas like hippocampus, a region in the brain, involved in learning/memory and is adversely affected in AD patients. Adult neurogenesis is primarily driven by committed neural progenitor cells that exist in low abundance within hippocampus. Given that mutant forms of PS1 have a great impact in initiation and progression of early onset forms of AD, it is of importance to examine whether they adversely affect neurogenesis in the adult brain. Our results provide insights on how mutant PS1-mediated alterations in plasma cytokines may have a detrimental effect on addition of new neurons in adult brain and support the notion that failure of neural progenitors to replace lost neurons in pathological situations may contribute to cognitive decline in AD.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    305—Beta and Gamma Secretase: BACE and Presenilin

    Monday, November 11, 2013, 8:00 am - 11:00 am

    305.03: Presenilin1 mutant-dependent alterations in plasma cytokines and signaling factors following environmental enrichment and the impact on adult hippocampal neurogenesis

    Location: 23A

    ">*K. VEERARAGHAVALU1, D. BERDNIK2, X. ZHANG1, T. WYSS-CORAY2, S. S. SISODIA1;
    1Univ. Chicago, CHICAGO, IL; 2The Dept. of Neurolog. Sci., Stanford Univ., Palo Alto, CA

    Abstract Body: Early-onset familial forms of the Alzheimer’s disease (FAD) are caused by inheritance of mutant genes encoding presenilin 1 (PS1) variants. We reported that ubiquitous expression of human FAD-linked PS1 variants in mice impairs environmental enrichment (EE)-induced adult hippocampal neural progenitor cell (AHNPC) proliferation and neuronal differentiation, and that microglia expressing PS1 variants secrete elevated level of cytokines and soluble factors, including: Eotaxin (CCL11), CXCL1, MIP2, TIMP1, Leptin, IGFBP6, that collectively impair the proliferation and differentiation phenotypes of wild-type AHNPCs in vitro (Choi et al., Neuron 2008). In view of our findings that non-CNS derived, blood-borne cytokines (e.g. Eotaxin) are elevated in the plasma of aging mice and are correlated with suppression of adult hippocampal neurogenesis (Villeda et al., Nature 2011), we sought to examine the profiles of cytokines and other immunomodulatory factors in the plasma from 2- or 6-month old transgenic mice expressing either human wild type PS1 (hPS1WT) or two different PS1 mutants following exposure to standard housing (SH) or EE-housing conditions. The relative concentrations of cytokines and signaling factors were measured using an antibody-based multiplex immunoassay. Preliminary analysis reveals that in comparison to SH animals, exposure of 2 month old hPS1WT mice to EE-conditions resulted in significant changes in the levels of 33 factors out of 403 tested (P < 0.05). For example, the levels of IL16, CCL12, CCL24, MMP9, CX3CL1, LRP4, LIF, FGFs (11, 12, & 13), TNFRSF (21 & 1B), Inhibin β-C chain and Prokineticin 1 were increased by at least 1.5-fold, while the levels of FASLG, FGF21 and IL17B were decreased by at least 1.5-fold. Notably, several of these factors have been positively correlated to neurogenesis in different experimental settings. We will present data that compare the levels of cytokines and signaling factors in the plasma of mice expressing hPS1WT to mice expressing PS1 variants that are exposed to SH and EE conditions. We anticipate that this unbiased multiplex screening approach will uncover factors that play a role in mediating mutant PS1-dependent impairments on EE-induced hippocampal neurogenesis.

    Lay Language Summary: We examined the proliferation status of adult neural progenitors in a mouse model that express human familial Alzheimer’s disease (FAD)-linked Presenilin 1 (PS1) mutants. Our results reveal that ubiquitous expression of PS1 variants in mice impairs environmental enrichment (EE)-induced adult hippocampal neural progenitor cell (AHNPC) proliferation and neuronal differentiation, and that microglia expressing PS1 variants secrete elevated level of cytokines that collectively impair the proliferation/differentiation phenotypes of wild-type AHNPCs in vitro. In view of our findings that non-CNS derived, blood-borne cytokines are elevated in the plasma of aging mice and are correlated with suppression of adult hippocampal neurogenesis, we examined the profiles of cytokines and other immunomodulatory factors in the plasma from transgenic mice expressing either human wild type PS1 (hPS1WT) or two different PS1 mutants following exposure to standard or EE-housing conditions. Our studies uncover factors that have been correlated to neurogenesis in different experimental settings and thus, may play a role in mediating mutant PS1-dependent impairments on EE-induced hippocampal neurogenesis.
    AD is the most common form of dementia characterized by progressive memory loss that seriously interferes with normal thinking, behavior and day-to-day activities. It is the fourth leading cause of death in elderly Americans and has become the strongest emotional burden for families with elderly parents are diagnosed with AD. Currently, there is no cure or a promising treatment strategy in place, which can stop progression of AD or improve memory loss. Considering the rising cost of healthcare, Scientists in around the world have invested efforts towards finding better ways to perform early diagnosis, prevent progression or treat this dreadful disease.
    At a pathological level, AD is characterized by gradual loss of neurons, deterioration of cognitive function, extracellular deposition of β-amyloid (Aβ) peptides and intra neuronal neurofibrillary tangles. Aβ are derived from larger amyloid precursor protein by the action of γ-secretase enzyme. PS1 is the catalytic component of γ-secretase. Intriguingly, a low percentage of diagnosed AD cases result from inheritance of mutations in Presenilin-1 gene, which pre-disposes them to disease symptoms as early as at the age of ~30 years. Understanding the normal functions of PS1 and the mechanisms by which mutated versions of this protein causes AD remains elusive, and is an area of active research for the past decade.
    The molecular mechanism(s) by which expression of mutant PS1 cause FAD are not fully understood, but the widely held view is that mutant PS1 enhances the ratio of Aβ42/Aβ40 peptides, leading to nucleation, oligomerization and neuropathogenicity of Aβ42 peptides. Notwithstanding this important aspect of pathogenesis mediated by FAD-linked PS1 variants, it is increasingly becoming clear that expression of mutant PS1 polypeptides have more global effects on neuronal function and pathophysiology. Of late, a pivotal role for PS1 was demonstrated in the context of neurogenesis that is sustained throughout the adult hood.
    Birth of new neurons take place throughout adult hood in certain specific areas like hippocampus, a region in the brain, involved in learning/memory and is adversely affected in AD patients. Adult neurogenesis is primarily driven by committed neural progenitor cells that exist in low abundance within hippocampus. Given that mutant forms of PS1 have a great impact in initiation and progression of early onset forms of AD, it is of importance to examine whether they adversely affect neurogenesis in the adult brain. Our results provide insights on how mutant PS1-mediated alterations in plasma cytokines may have a detrimental effect on addition of new neurons in adult brain and support the notion that failure of neural progenitors to replace lost neurons in pathological situations may contribute to cognitive decline in AD.