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| ======== Alzheimer's Disease ======== | ======== Alzheimer's Disease ======== | ||
| + | Presentation File: {{::alzheimer.pdf|}} | ||
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| ===== Introduction ===== | ===== Introduction ===== | ||
| Alzheimer’s disease (AD) is an irreversible brain disorder that is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory (Alzheimer’s Disease, 2016). Alzheimer’s is the most common neurodegenerative disorder, and is the sixth leading cause of death in the United States (Alzheimer’s Disease, 2016). The greatest known risk factor is increasing age, however Alzheimer’s is not a normal part of aging as one can also develop early-onset Alzheimer’s in their 40s or 50s of age (Alzheimer’s Disease, 2016). Alzheimer’s disease is a degeneration of neurons in the brain, starting in the temporal lobe and spreads to parietal, and frontal lobe(Alzheimer’s Disease, 2016)). The overall mass of the brain is reduced as a result of cell death, and the degeneration of neurons (Alzheimer’s Disease, 2016)). Alzheimer’s disease is progressive, and has three stages : early, mild to moderate, and severe (Alzheimer’s Disease, 2016)). In the earlier stages, memory loss is mild compared to the late stages, where the ability to carry a conversation and respond to the environment is completely impaired, resulting in complete dependence on others for care (Alzheimer’s Disease, 2016). There is no cure for Alzheimer’s that stops the progression completely, however treatments are available for the symptoms and can temporarily slow the worsening of the symptoms, and improve quality of life (Alzheimer’s Disease, 2016). | Alzheimer’s disease (AD) is an irreversible brain disorder that is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory (Alzheimer’s Disease, 2016). Alzheimer’s is the most common neurodegenerative disorder, and is the sixth leading cause of death in the United States (Alzheimer’s Disease, 2016). The greatest known risk factor is increasing age, however Alzheimer’s is not a normal part of aging as one can also develop early-onset Alzheimer’s in their 40s or 50s of age (Alzheimer’s Disease, 2016). Alzheimer’s disease is a degeneration of neurons in the brain, starting in the temporal lobe and spreads to parietal, and frontal lobe(Alzheimer’s Disease, 2016)). The overall mass of the brain is reduced as a result of cell death, and the degeneration of neurons (Alzheimer’s Disease, 2016)). Alzheimer’s disease is progressive, and has three stages : early, mild to moderate, and severe (Alzheimer’s Disease, 2016)). In the earlier stages, memory loss is mild compared to the late stages, where the ability to carry a conversation and respond to the environment is completely impaired, resulting in complete dependence on others for care (Alzheimer’s Disease, 2016). There is no cure for Alzheimer’s that stops the progression completely, however treatments are available for the symptoms and can temporarily slow the worsening of the symptoms, and improve quality of life (Alzheimer’s Disease, 2016). | ||
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| Tau is a soluble microtubule-binding protein. One of the functions of Tau is to stabilize microtubules in axons for axonal transport, and as cytoskeletal elements for growth (Citron, 2010). One of the characteristics observed in AD neurons consist of hyperphosphorylated, aggregated insoluble tau (Citron, 2010). This leads to direct toxic effects such as a loss of axonal transport as tau can be detached from microtubules leading to the formation of soluble tau aggregates forming neurofibrillary tangles (Citron, 2010). Current therapeutic strategies focus on the inhibition of tau aggregation, and to block tau hyperphosphorylation (Citron, 2010). One of these strategies is to design kinase inhibitors, which would prevent hyperphosphorylation, and design aggregation inhibitors that would block the soluble tau aggregates and formation of tangles (Citron, 2010). Tau toxicity can also be prevented by enhancing clearance of tau, and degradation of tau aggregates (Citron, 2010). | Tau is a soluble microtubule-binding protein. One of the functions of Tau is to stabilize microtubules in axons for axonal transport, and as cytoskeletal elements for growth (Citron, 2010). One of the characteristics observed in AD neurons consist of hyperphosphorylated, aggregated insoluble tau (Citron, 2010). This leads to direct toxic effects such as a loss of axonal transport as tau can be detached from microtubules leading to the formation of soluble tau aggregates forming neurofibrillary tangles (Citron, 2010). Current therapeutic strategies focus on the inhibition of tau aggregation, and to block tau hyperphosphorylation (Citron, 2010). One of these strategies is to design kinase inhibitors, which would prevent hyperphosphorylation, and design aggregation inhibitors that would block the soluble tau aggregates and formation of tangles (Citron, 2010). Tau toxicity can also be prevented by enhancing clearance of tau, and degradation of tau aggregates (Citron, 2010). | ||
| - | <box 65% round centre | > {{ :screen_shot_2017-10-29_at_1.10.29_am.png |}} </box| Figure 12: > | + | <box 65% round centre | > {{ :screen_shot_2017-10-29_at_1.10.29_am.png |}} </box| Figure 12: Tau pathology and therapeutic approaches such as designing kinase inhibitors and aggregation inhibitors to prevent the formation of tau tangles (Citron, 2010). > |
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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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| ===== References ===== | ===== References ===== | ||
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