Pritam das - Academia.edu (original) (raw)
Papers by Pritam das
Journal of neuroinflammation, Jan 26, 2006
Microglial activation has been proposed to facilitate clearance of amyloid beta protein (Abeta) f... more Microglial activation has been proposed to facilitate clearance of amyloid beta protein (Abeta) from the brain following Abeta immunotherapy in amyloid precursor protein (APP) transgenic mice. Interleukin-1 receptor 1 knockout (IL-1 R1-/-) mice are reported to exhibit blunted inflammatory responses to injury. To further define the role of IL-1-mediated inflammatory responses and microglial activation in this paradigm, we examined the efficacy of passive Abeta immunotherapy in Tg2576 mice crossed into the IL-1 R1-/- background. In addition, we examined if loss of IL-1 R1-/- modifies Abeta deposition in the absence of additional manipulations. We passively immunized Tg2576 mice crossed into the IL-1 R1-/- background (APP/IL-1 R1-/- mice) with an anti-Abeta1-16 mAb (mAb9, IgG2a) that we previously showed could attenuate Abeta deposition in Tg2576 mice. We also examined whether the IL-1 R1 knockout background modifies Abeta deposition in untreated mice. Biochemical and immunohistochemic...
Vaccine, 2006
We describe a study testing fibrillar -amyloid 1-42 (A 42) vaccination in dogs. Three young bea... more We describe a study testing fibrillar -amyloid 1-42 (A 42) vaccination in dogs. Three young beagles (4.6 years) were immunized twice with A 42 and a Th1 adjuvant (TiterMax Gold). Animals generated primarily IgG 2 and IgM antibody responses, which were specific for the A 11-30 region of A 1-42. Next, 3 aged beagles (8.9-13.8 years) were immunized 4 times with A 42 and a Th2 adjuvant (Alum). We observed an acute increase in IgG 2, a slower increase in IgG 1 and A antibodies of broader specificity (A 1-15> A 11-30> A 6-20). A nonsignificant increase in CSF A 1-40 and decrease in A 1-40/1-42 in cortex was detected. Canines may be a useful system for testing an A vaccine.
Neuron, 2005
(C31) can be neurotoxic (Lu et al., 1 Department Neuroscience 2000; Mattson, 2004; Yankner et al.... more (C31) can be neurotoxic (Lu et al., 1 Department Neuroscience 2000; Mattson, 2004; Yankner et al., 1989). Moreover Mayo Clinic College of Medicine APP and fragments such as the APP intracellular do-Jacksonville, Florida 32224 main have signaling functions that may also contribute 2 Department of Human Genetics to a phenotype (LaFerla, 2002). Consequently, mice that Mount Sinai School of Medicine overexpress individual Aβ peptides in the absence of New York, New York 10029 overexpression of APP allow testing of hypotheses re-3 Laboratory of Neurogenetics garding (1) the role of select Aβ species in the initiation National Institute on Aging and propagation of amyloid deposition in vivo and (2) National Institutes of Health the specific contribution of each Aβ peptide to the phe-Bethesda, Maryland 20892 notype seen in AD mouse models. Much of the data that support a pivotal role for Aβ42 in AD have come from the study of mutations in the Summary APP and presenilin genes that cause early-onset familial forms of AD (Selkoe, 1998). The vast majority of Considerable circumstantial evidence suggests that these mutations selectively increase the relative levels A42 is the initiating molecule in Alzheimer's disease of Aβ42. However, even in typical late-onset AD there (AD) pathogenesis. However, the absolute requireis evidence that Aβ42, a minor Aβ species, usually repment for A42 for amyloid deposition has never been resenting less then 20% of the total Aβ secreted, is both demonstrated in vivo. We have addressed this by dethe earliest form and the predominant species deposveloping transgenic models that express A1-40 or ited in the brain parenchyma (Golde et al., 2000). In A1-42 in the absence of human amyloid  protein contrast, Aβ40, the major Aβ peptide secreted by cells, precursor (APP) overexpression. Mice expressing appears to be the predominant species deposited in high levels of A1-40 do not develop overt amyloid the amyloid deposits in the cerebral vasculature (conpathology. In contrast, mice expressing lower levels gophillic angiopathy, CAA) (Gravina et al., 1995; Iwatof A1-42 accumulate insoluble A1-42 and develop subo et al., 1994). Transgenic mouse studies using mucompact amyloid plaques, congophilic amyloid angitant APP and PS transgenes have provided some opathy (CAA), and diffuse A deposits. When mice insights into the effects that altering the ratio of Aβ40 expressing A1-42 are crossed with mutant APP and Aβ42 have on time to onset of deposition, type of (Tg2576) mice, there is also a massive increase in amdeposit (e.g., diffuse versus compact), and extent of yloid deposition. These data establish that A1-42 is CAA (Borchelt et al., 1997; Herzig et al., 2004; Holcomb essential for amyloid deposition in the parenchyma et al., 1998). However, such studies have not definitively and also in vessels. identified which Aβ species are responsible for seeding amyloid deposition in either the parenchyma or vascu-Introduction lature. To address this question, we have generated trans-Overexpression of Alzheimer's disease (AD)-linked mugenic mice that express Aβ1-40 or Aβ1-42 without APP tant human APP transgenes has been the most reliable overexpression. For these studies we used cDNAs that means of promoting deposition of Aβ in the brains of express fusion proteins between the BRI protein, intransgenic mice. As they age, these mutant APP mice volved in amyloid deposition in Familial British (FBD) develop robust amyloid pathology and other AD-like and Danish Dementia (FDD) and Aβ1-40 (BRI-Aβ40) or features, including decreased synaptic density, reactive Aβ1-42 (BRI-Aβ42) (Lewis et al., 2001; Vidal et al., 1999, gliosis, and some cognitive deficits. However, these 2000) (Figure 1A). We have previously shown that transmutant APP mouse models show little evidence of fection of BRI-Aβ cDNAs results in high-level expresovert neuronal loss and neurofibrillary tangle (NFT) sion and secretion of the encoded Aβ peptide through pathology (Hardy and Selkoe, 2002; Price et al., 1998). proteolytic cleavage of the fusion protein at a furin One potential problem with most of the widely studied cleavage site immediately preceding Aβ (Lewis et al., mutant APP mice is that the high level of overexpres-2001). Efficient secretion of Aβ from the BRI fusion prosion of mutant human APP may confound the phenotein distinguishes this approach from studies using Aβ minigene constructs that generate high levels of intra
Neurobiology of Aging, 2000
Molecular Neurodegeneration, 2012
Background Transgenic mice expressing disease-associated proteins have become standard tools for ... more Background Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder. Results We show that overexpression of the Alzheimer’s-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when m...
CNS & Neurological Disorders - Drug Targets, 2009
There is substantial and compelling evidence that aggregation and accumulation of amyloid beta pr... more There is substantial and compelling evidence that aggregation and accumulation of amyloid beta protein (Abeta) plays a pivotal role in the development of Alzheimer's disease (AD); thus, numerous strategies to prevent Abeta aggregation and accumulation or to facilitate removal of preexisting deposits of Abeta are being evaluated as ways to treat or prevent AD. Pre-clinical studies in mice demonstrate the therapeutic potential of altering Abeta deposition by inducing a humoral immune response to fibrillar Abeta42 (fAbeta42) or passively administering anti-Abeta antibodies (Abs), and both passive and active anti-Abeta immunotherapeutic approaches are now being tested in humans. Although a variety of mechanisms have been postulated regarding how Abeta immunotherapy might work to attenuate or in some circumstances clear Abeta from the brain, no mechanism has been definitively proven or disproven. Herein, we will review the various mechanisms that have been postulated. In addition we will discuss how a more thorough understanding of the pharmacokinetics of anti-Abeta Abs and their effects on Abeta levels and turnover provides insight into both the therapeutic potential and limitation of Abeta immunotherapy. We will conclude with a discussion of additional experimentation required to better understand the mechanism of action of anti-Abeta Abs in AD and optimize antibody (Ab) mediated therapy for AD.
Blood, 2008
Notch and its ligands have been implicated in the regulation and differentiation of various CD4+ ... more Notch and its ligands have been implicated in the regulation and differentiation of various CD4+ T-helper cells. Regulatory T cells (Tregs), which express the transcription factor Foxp3, suppress aberrant immune responses that are typically associated with autoimmunity or excessive inflammation. Previous studies have shown that transforming growth factor beta (TGFβ1) induces Foxp3 expression and a regulatory phenotype in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling using γ-secretase inhibitor (GSI) treatment blocks (1) TGFβ1-induced Foxp3 expression, (2) the up-regulation of Foxp3-target genes, and (3) the ability to suppress naive T-cell proliferation. In addition, the binding of Notch1, CSL, and Smad to conserved binding sites in the foxp3 promoter can be inhibited by treatment with GSI. Finally, in vivo administration of GSI results in reduced Foxp3 expression and development of symptoms consistent with autoimmune hepatitis, a disease previou...
Bioorganic & Medicinal Chemistry Letters, 2007
An improved chemical synthesis of N-2((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-m... more An improved chemical synthesis of N-2((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-L-alaninamide (LY411,575, 9a), a known γ-secretase inhibitor, is described. The key synthetic steps, which used no chiral chromatography in the entire sequence, involved 1) improved microwave-assisted synthesis of a seven-membered lactam (±)-(5,7-dihydro-6H-dibenz-[b,d]azepin-6-one 2, and, 2) convenient isolation of pure LY411575 from a mixture of four diastereomers by simple flash silica gel chromatography. Starting from the resolved aminolactams 5a and 5b, all four diastereomers were produced in enantiomerically pure form.
Alzheimer's & Dementia, 2006
immunoreactivity is significantly reduced in 2.5 month mice well before significant neuronal cell... more immunoreactivity is significantly reduced in 2.5 month mice well before significant neuronal cell loss is observed but where spatial reference memory displays variable deficits. Conclusion: The memory deficits in the rTg4510 mice appear to result from changes in neuronal function rather than overall neuronal death. Initial results suggest that synaptic degeneration pre-dates neuronal loss by several months. We therefore hypothesize that memory deficits in rTg4510 mice may be due at least in part to a synaptic disorder that is reversible upon suppression of mutant tau.
Alzheimer's & Dementia, 2010
Many new therapeutics for Alzheimer's disease delay the accumulation of Aβ in transgenic mice, bu... more Many new therapeutics for Alzheimer's disease delay the accumulation of Aβ in transgenic mice, but evidence for clearance of pre-existing plaques is often lacking. Here we demonstrate that anti-Aβ immunotherapy combined with suppression of Aβ synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP mice with doxycycline to suppress transgenic Aβ production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterwards to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and Aβ42 content by 28% relative to pre-treatment levels, with preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. We demonstrate that peripherally administered anti-Aβ antibody crossed the blood-brain barrier, bound to plaques, and was still be found associated with a subset of amyloid deposits many months after the final injection. Antibody accessed the brain independent of plasma Aβ levels, where it enhanced microglial internalization of aggregated Aβ. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated Aβ, but is opposed by the continued aggregation of newly secreted Aβ. By arresting the production of Aβ, combination therapy allows microglial clearance to work from a static amyloid burden towards a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.
Alzheimer's & Dementia, 2008
Alzheimer's & Dementia, 2006
Alzheimer's & Dementia, 2006
Journal of neuroinflammation, Jan 26, 2006
Microglial activation has been proposed to facilitate clearance of amyloid beta protein (Abeta) f... more Microglial activation has been proposed to facilitate clearance of amyloid beta protein (Abeta) from the brain following Abeta immunotherapy in amyloid precursor protein (APP) transgenic mice. Interleukin-1 receptor 1 knockout (IL-1 R1-/-) mice are reported to exhibit blunted inflammatory responses to injury. To further define the role of IL-1-mediated inflammatory responses and microglial activation in this paradigm, we examined the efficacy of passive Abeta immunotherapy in Tg2576 mice crossed into the IL-1 R1-/- background. In addition, we examined if loss of IL-1 R1-/- modifies Abeta deposition in the absence of additional manipulations. We passively immunized Tg2576 mice crossed into the IL-1 R1-/- background (APP/IL-1 R1-/- mice) with an anti-Abeta1-16 mAb (mAb9, IgG2a) that we previously showed could attenuate Abeta deposition in Tg2576 mice. We also examined whether the IL-1 R1 knockout background modifies Abeta deposition in untreated mice. Biochemical and immunohistochemic...
Vaccine, 2006
We describe a study testing fibrillar -amyloid 1-42 (A 42) vaccination in dogs. Three young bea... more We describe a study testing fibrillar -amyloid 1-42 (A 42) vaccination in dogs. Three young beagles (4.6 years) were immunized twice with A 42 and a Th1 adjuvant (TiterMax Gold). Animals generated primarily IgG 2 and IgM antibody responses, which were specific for the A 11-30 region of A 1-42. Next, 3 aged beagles (8.9-13.8 years) were immunized 4 times with A 42 and a Th2 adjuvant (Alum). We observed an acute increase in IgG 2, a slower increase in IgG 1 and A antibodies of broader specificity (A 1-15> A 11-30> A 6-20). A nonsignificant increase in CSF A 1-40 and decrease in A 1-40/1-42 in cortex was detected. Canines may be a useful system for testing an A vaccine.
Neuron, 2005
(C31) can be neurotoxic (Lu et al., 1 Department Neuroscience 2000; Mattson, 2004; Yankner et al.... more (C31) can be neurotoxic (Lu et al., 1 Department Neuroscience 2000; Mattson, 2004; Yankner et al., 1989). Moreover Mayo Clinic College of Medicine APP and fragments such as the APP intracellular do-Jacksonville, Florida 32224 main have signaling functions that may also contribute 2 Department of Human Genetics to a phenotype (LaFerla, 2002). Consequently, mice that Mount Sinai School of Medicine overexpress individual Aβ peptides in the absence of New York, New York 10029 overexpression of APP allow testing of hypotheses re-3 Laboratory of Neurogenetics garding (1) the role of select Aβ species in the initiation National Institute on Aging and propagation of amyloid deposition in vivo and (2) National Institutes of Health the specific contribution of each Aβ peptide to the phe-Bethesda, Maryland 20892 notype seen in AD mouse models. Much of the data that support a pivotal role for Aβ42 in AD have come from the study of mutations in the Summary APP and presenilin genes that cause early-onset familial forms of AD (Selkoe, 1998). The vast majority of Considerable circumstantial evidence suggests that these mutations selectively increase the relative levels A42 is the initiating molecule in Alzheimer's disease of Aβ42. However, even in typical late-onset AD there (AD) pathogenesis. However, the absolute requireis evidence that Aβ42, a minor Aβ species, usually repment for A42 for amyloid deposition has never been resenting less then 20% of the total Aβ secreted, is both demonstrated in vivo. We have addressed this by dethe earliest form and the predominant species deposveloping transgenic models that express A1-40 or ited in the brain parenchyma (Golde et al., 2000). In A1-42 in the absence of human amyloid  protein contrast, Aβ40, the major Aβ peptide secreted by cells, precursor (APP) overexpression. Mice expressing appears to be the predominant species deposited in high levels of A1-40 do not develop overt amyloid the amyloid deposits in the cerebral vasculature (conpathology. In contrast, mice expressing lower levels gophillic angiopathy, CAA) (Gravina et al., 1995; Iwatof A1-42 accumulate insoluble A1-42 and develop subo et al., 1994). Transgenic mouse studies using mucompact amyloid plaques, congophilic amyloid angitant APP and PS transgenes have provided some opathy (CAA), and diffuse A deposits. When mice insights into the effects that altering the ratio of Aβ40 expressing A1-42 are crossed with mutant APP and Aβ42 have on time to onset of deposition, type of (Tg2576) mice, there is also a massive increase in amdeposit (e.g., diffuse versus compact), and extent of yloid deposition. These data establish that A1-42 is CAA (Borchelt et al., 1997; Herzig et al., 2004; Holcomb essential for amyloid deposition in the parenchyma et al., 1998). However, such studies have not definitively and also in vessels. identified which Aβ species are responsible for seeding amyloid deposition in either the parenchyma or vascu-Introduction lature. To address this question, we have generated trans-Overexpression of Alzheimer's disease (AD)-linked mugenic mice that express Aβ1-40 or Aβ1-42 without APP tant human APP transgenes has been the most reliable overexpression. For these studies we used cDNAs that means of promoting deposition of Aβ in the brains of express fusion proteins between the BRI protein, intransgenic mice. As they age, these mutant APP mice volved in amyloid deposition in Familial British (FBD) develop robust amyloid pathology and other AD-like and Danish Dementia (FDD) and Aβ1-40 (BRI-Aβ40) or features, including decreased synaptic density, reactive Aβ1-42 (BRI-Aβ42) (Lewis et al., 2001; Vidal et al., 1999, gliosis, and some cognitive deficits. However, these 2000) (Figure 1A). We have previously shown that transmutant APP mouse models show little evidence of fection of BRI-Aβ cDNAs results in high-level expresovert neuronal loss and neurofibrillary tangle (NFT) sion and secretion of the encoded Aβ peptide through pathology (Hardy and Selkoe, 2002; Price et al., 1998). proteolytic cleavage of the fusion protein at a furin One potential problem with most of the widely studied cleavage site immediately preceding Aβ (Lewis et al., mutant APP mice is that the high level of overexpres-2001). Efficient secretion of Aβ from the BRI fusion prosion of mutant human APP may confound the phenotein distinguishes this approach from studies using Aβ minigene constructs that generate high levels of intra
Neurobiology of Aging, 2000
Molecular Neurodegeneration, 2012
Background Transgenic mice expressing disease-associated proteins have become standard tools for ... more Background Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder. Results We show that overexpression of the Alzheimer’s-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when m...
CNS & Neurological Disorders - Drug Targets, 2009
There is substantial and compelling evidence that aggregation and accumulation of amyloid beta pr... more There is substantial and compelling evidence that aggregation and accumulation of amyloid beta protein (Abeta) plays a pivotal role in the development of Alzheimer's disease (AD); thus, numerous strategies to prevent Abeta aggregation and accumulation or to facilitate removal of preexisting deposits of Abeta are being evaluated as ways to treat or prevent AD. Pre-clinical studies in mice demonstrate the therapeutic potential of altering Abeta deposition by inducing a humoral immune response to fibrillar Abeta42 (fAbeta42) or passively administering anti-Abeta antibodies (Abs), and both passive and active anti-Abeta immunotherapeutic approaches are now being tested in humans. Although a variety of mechanisms have been postulated regarding how Abeta immunotherapy might work to attenuate or in some circumstances clear Abeta from the brain, no mechanism has been definitively proven or disproven. Herein, we will review the various mechanisms that have been postulated. In addition we will discuss how a more thorough understanding of the pharmacokinetics of anti-Abeta Abs and their effects on Abeta levels and turnover provides insight into both the therapeutic potential and limitation of Abeta immunotherapy. We will conclude with a discussion of additional experimentation required to better understand the mechanism of action of anti-Abeta Abs in AD and optimize antibody (Ab) mediated therapy for AD.
Blood, 2008
Notch and its ligands have been implicated in the regulation and differentiation of various CD4+ ... more Notch and its ligands have been implicated in the regulation and differentiation of various CD4+ T-helper cells. Regulatory T cells (Tregs), which express the transcription factor Foxp3, suppress aberrant immune responses that are typically associated with autoimmunity or excessive inflammation. Previous studies have shown that transforming growth factor beta (TGFβ1) induces Foxp3 expression and a regulatory phenotype in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling using γ-secretase inhibitor (GSI) treatment blocks (1) TGFβ1-induced Foxp3 expression, (2) the up-regulation of Foxp3-target genes, and (3) the ability to suppress naive T-cell proliferation. In addition, the binding of Notch1, CSL, and Smad to conserved binding sites in the foxp3 promoter can be inhibited by treatment with GSI. Finally, in vivo administration of GSI results in reduced Foxp3 expression and development of symptoms consistent with autoimmune hepatitis, a disease previou...
Bioorganic & Medicinal Chemistry Letters, 2007
An improved chemical synthesis of N-2((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-m... more An improved chemical synthesis of N-2((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-L-alaninamide (LY411,575, 9a), a known γ-secretase inhibitor, is described. The key synthetic steps, which used no chiral chromatography in the entire sequence, involved 1) improved microwave-assisted synthesis of a seven-membered lactam (±)-(5,7-dihydro-6H-dibenz-[b,d]azepin-6-one 2, and, 2) convenient isolation of pure LY411575 from a mixture of four diastereomers by simple flash silica gel chromatography. Starting from the resolved aminolactams 5a and 5b, all four diastereomers were produced in enantiomerically pure form.
Alzheimer's & Dementia, 2006
immunoreactivity is significantly reduced in 2.5 month mice well before significant neuronal cell... more immunoreactivity is significantly reduced in 2.5 month mice well before significant neuronal cell loss is observed but where spatial reference memory displays variable deficits. Conclusion: The memory deficits in the rTg4510 mice appear to result from changes in neuronal function rather than overall neuronal death. Initial results suggest that synaptic degeneration pre-dates neuronal loss by several months. We therefore hypothesize that memory deficits in rTg4510 mice may be due at least in part to a synaptic disorder that is reversible upon suppression of mutant tau.
Alzheimer's & Dementia, 2010
Many new therapeutics for Alzheimer's disease delay the accumulation of Aβ in transgenic mice, bu... more Many new therapeutics for Alzheimer's disease delay the accumulation of Aβ in transgenic mice, but evidence for clearance of pre-existing plaques is often lacking. Here we demonstrate that anti-Aβ immunotherapy combined with suppression of Aβ synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP mice with doxycycline to suppress transgenic Aβ production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterwards to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and Aβ42 content by 28% relative to pre-treatment levels, with preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. We demonstrate that peripherally administered anti-Aβ antibody crossed the blood-brain barrier, bound to plaques, and was still be found associated with a subset of amyloid deposits many months after the final injection. Antibody accessed the brain independent of plasma Aβ levels, where it enhanced microglial internalization of aggregated Aβ. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated Aβ, but is opposed by the continued aggregation of newly secreted Aβ. By arresting the production of Aβ, combination therapy allows microglial clearance to work from a static amyloid burden towards a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.
Alzheimer's & Dementia, 2008
Alzheimer's & Dementia, 2006
Alzheimer's & Dementia, 2006