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group_1_presentation_2_-alzheimer_s_disease [2017/11/04 00:51] tariqm2 [Targeting Tau Aggregates] |
group_1_presentation_2_-alzheimer_s_disease [2018/01/25 15:18] (current) |
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| Over the past few years, amyloid-β (Aβ) immunotherapy have become a fascinating area of research in AD. Research in this field was initiated after the publication of the first immunization paper from Elan that reported that amyloid pathology was reduced in an APP transgenic mouse model after vaccination with aggregated Aβ (Citron, 2010). Three hypotheses have been proposed regarding Aβ immunotherapy mechanism. The first mechanism (Figure A) is based on microglial activation and phagocytosis. In this mechanism, amyloid-specific antibodies are administered and reach the central nervous system, bind to amyloid deposits (plaque), and trigger microglia to phaocytose the amyloid (Citron, 2010). The second mechanism (Figure B) is a direct interact interaction of amyloid-specific antibodies with the amyloid deposits. The antibodies are able to resolve the in vitro aggregated Aβ, however research is still being done on how the amounts of antibody administered can dissolve the existing insoluble fibrils in the brain (Citron, 2010). A follow-up mechanism was proposed, in which peripheral amyloid-specific antibodies act as a sink (Figure C), and pull soluble Aβ into periphery where it is cleared (Citron, 2010). In vivo studies identified an efficient receptor-mediated transport mechanism for Aβ at the blood brain barrier, where Aβ is transported from CNS to plasma, and from plasma to CNS (Demattos, Bales, Cummins, Dodart, Paul & Holtzman, 2001). Research data suggests that to alter the CNS Aβ levels, increase efflux of Aβ from CNS to plasma and/or decrease efflux of Aβ from plasma to CNS is needed (Demattos et al., 2001). The experiment demonstrated that the Aβ monoclonal antibody 266 (m266) showed affinity to soluble Aβ, and did not bind to plaques (Demattos et al., 2001). This reduced the amyloid levels upon administration. It was concluded that sufficient antibody concentrations were required to produce noticeable levels of cerebrospinal fluid capture needed to capture soluble Aβ, and produce a net flux of Aβ from the CNS to periphery, leading to decreased amyloid levels (Citron, 2010). Although peripheral administration of m266 reduced Aβ deposition, m266 did not bind to the deposits (Demattos et al., 2001). Hence, m266 appears to reduce brain Aβ burden by altering the CNS and plasma Aβ clearance (Demattos et al., 2001). | Over the past few years, amyloid-β (Aβ) immunotherapy have become a fascinating area of research in AD. Research in this field was initiated after the publication of the first immunization paper from Elan that reported that amyloid pathology was reduced in an APP transgenic mouse model after vaccination with aggregated Aβ (Citron, 2010). Three hypotheses have been proposed regarding Aβ immunotherapy mechanism. The first mechanism (Figure A) is based on microglial activation and phagocytosis. In this mechanism, amyloid-specific antibodies are administered and reach the central nervous system, bind to amyloid deposits (plaque), and trigger microglia to phaocytose the amyloid (Citron, 2010). The second mechanism (Figure B) is a direct interact interaction of amyloid-specific antibodies with the amyloid deposits. The antibodies are able to resolve the in vitro aggregated Aβ, however research is still being done on how the amounts of antibody administered can dissolve the existing insoluble fibrils in the brain (Citron, 2010). A follow-up mechanism was proposed, in which peripheral amyloid-specific antibodies act as a sink (Figure C), and pull soluble Aβ into periphery where it is cleared (Citron, 2010). In vivo studies identified an efficient receptor-mediated transport mechanism for Aβ at the blood brain barrier, where Aβ is transported from CNS to plasma, and from plasma to CNS (Demattos, Bales, Cummins, Dodart, Paul & Holtzman, 2001). Research data suggests that to alter the CNS Aβ levels, increase efflux of Aβ from CNS to plasma and/or decrease efflux of Aβ from plasma to CNS is needed (Demattos et al., 2001). The experiment demonstrated that the Aβ monoclonal antibody 266 (m266) showed affinity to soluble Aβ, and did not bind to plaques (Demattos et al., 2001). This reduced the amyloid levels upon administration. It was concluded that sufficient antibody concentrations were required to produce noticeable levels of cerebrospinal fluid capture needed to capture soluble Aβ, and produce a net flux of Aβ from the CNS to periphery, leading to decreased amyloid levels (Citron, 2010). Although peripheral administration of m266 reduced Aβ deposition, m266 did not bind to the deposits (Demattos et al., 2001). Hence, m266 appears to reduce brain Aβ burden by altering the CNS and plasma Aβ clearance (Demattos et al., 2001). | ||
| - | <box 65% round centre | > {{ ::screen_shot_2017-10-29_at_1.18.26_am.png |}} </box| Figure 13: > | + | <box 65% round centre | > {{ ::screen_shot_2017-10-29_at_1.18.26_am.png |}} </box| Figure 13: Four models of antibody-mediated amyloid clearance proposed as a future therapeutic to clear amyloid-beta plaques (Citron, 2010). > |
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| Alzheimer’s Association. (n.d). Stages of Alzheimer’s & Symptoms. Retreived October 26, 2017, from https://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp?type=brainTourFooter#overview | Alzheimer’s Association. (n.d). Stages of Alzheimer’s & Symptoms. Retreived October 26, 2017, from https://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp?type=brainTourFooter#overview | ||
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| + | Alzheimer's Disease and Related Dementias. (2016, August). Retrieved October 23, 2017, from | ||
| + | https://www.nia.nih.gov/health/alzheimer | ||
| Anand, R., Gill, K. D., & Mahdi, A. A. (2014). Therapeutics of Alzheimer’s Disease: Past, Present and Future. Neuropharmacology, 76, 27–50. https://doi.org/10.1016/j.neuropharm.2013.07.004 | Anand, R., Gill, K. D., & Mahdi, A. A. (2014). Therapeutics of Alzheimer’s Disease: Past, Present and Future. Neuropharmacology, 76, 27–50. https://doi.org/10.1016/j.neuropharm.2013.07.004 | ||
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| Clement, F., & Belleville, S. (2009). Test-retest reliability of fMRI verbal episodic memory paradigms in healthy older adults and in persons with mild cognitive impairment. Hum Brain Mapp, 30, 4033–4047 | Clement, F., & Belleville, S. (2009). Test-retest reliability of fMRI verbal episodic memory paradigms in healthy older adults and in persons with mild cognitive impairment. Hum Brain Mapp, 30, 4033–4047 | ||
| Delacourte, A., & Defossez, A. (1986). Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. Journal of the neurological sciences, 76(2), 173-186. | Delacourte, A., & Defossez, A. (1986). Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. Journal of the neurological sciences, 76(2), 173-186. | ||
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| + | DeMattos, R. B., Bales, K. R., Cummins, D. J., Dodart, J.-C., Paul, S. M., & Holtzman, D. M. (2001). Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 98(15), 8850–8855. http://doi.org/10.1073/pnas.151261398 | ||
| Ellis, J. M. (2005). Cholinesterase inhibitors in the treatment of dementia. The Journal of the American Osteopathic Association, 105(3), 145–158. https://doi.org/10.7556/JAOA.2005.105.3.145 | Ellis, J. M. (2005). Cholinesterase inhibitors in the treatment of dementia. The Journal of the American Osteopathic Association, 105(3), 145–158. https://doi.org/10.7556/JAOA.2005.105.3.145 | ||
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| Hansen, R. A., Gartlehner, G., Webb, A. P., Morgan, L. C., Moore, C. G., & Jonas, D. E. (2008). Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: A systematic review and meta-analysis. Clin. Interventions Aging, 3(2), 211–225. | Hansen, R. A., Gartlehner, G., Webb, A. P., Morgan, L. C., Moore, C. G., & Jonas, D. E. (2008). Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: A systematic review and meta-analysis. Clin. Interventions Aging, 3(2), 211–225. | ||
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| Marcus, C., Mena, E., & Subramaniam, R. M. (2014). Brain PET in the Diagnosis of Alzheimer’s Disease. Clin Nucl Med, 39(10), e413–e426. http://doi.org/10.1097/RLU.0000000000000547 | Marcus, C., Mena, E., & Subramaniam, R. M. (2014). Brain PET in the Diagnosis of Alzheimer’s Disease. Clin Nucl Med, 39(10), e413–e426. http://doi.org/10.1097/RLU.0000000000000547 | ||
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| + | Mayeux, R., & Stern, Y. (2012). Epidemiology of Alzheimer Disease. Cold Spring Harbor Perspectives in Medicine, 2(8), 10.1101/cshperspect.a006239 a006239. http://doi.org/10.1101/cshperspect.a006239 | ||
| Putcha D, O’Keefe K, LaViolette P, O’Brien J, Greve D, Rentz D, Locascio JJ, Atri A, Sperling R (2010). Reliability of fMRI associative encoding memory paradigm in non-demented elderly adults. Hum Brain Mapp, 32(12), 2027-44. | Putcha D, O’Keefe K, LaViolette P, O’Brien J, Greve D, Rentz D, Locascio JJ, Atri A, Sperling R (2010). Reliability of fMRI associative encoding memory paradigm in non-demented elderly adults. Hum Brain Mapp, 32(12), 2027-44. | ||
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| + | Reitz, C., Brayne, C., & Mayeux, R. (2011). Epidemiology of Alzheimer disease. Nature Reviews. Neurology, 7(3), 137–152. http://doi.org/10.1038/nrneurol.2011.2 | ||
| Rocher, A.B., Chapon, F., Blaizot, X., Baron, J.C., Chavoix, C. (2003). Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: A study in baboons. Neuroimage 20, 1894–1898 | Rocher, A.B., Chapon, F., Blaizot, X., Baron, J.C., Chavoix, C. (2003). Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: A study in baboons. Neuroimage 20, 1894–1898 | ||
