Intravenous Immunoglobulin (IVIG) Treatment Exerts Antioxidant and Neuropreservatory Effects in Preclinical Models of Alzheimer’s Disease

Counts, Scott; Ray, Balmiki; Mufson, Elliott J.; Perez, Sylvia E.; He, Bin; Lahiri, Debomoy K.

doi:10.1007/s10875-014-0020-9

Cited by 19 publications

(12 citation statements)

References 25 publications

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“…For example, Gammagard, a formulation of human immunoglobulins, has been tested in both AD models and patients (39,40). In mouse models, these studies have shown that IgGs can reduce Aβ levels especially when directly injected into the brain (38,41), and our own data have confirmed these findings. However, despite promising phase II results, a phase III clinical trial of Gammagard in mild-to-moderate AD patients failed to improve cognition.…”

Section: Discussionsupporting

confidence: 66%

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

318

257

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The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptiveinnate immunity cross talk and accelerated disease progression.is the leading cause of age-related neurodegeneration, affecting over 5.2 million people in the United States alone (1). Pathologically, AD is characterized by two hallmark protein aggregates, amyloid-β (Aβ) plaques and neurofibrillary tangles, that are accompanied by neuroinflammation, including microgliosis, elevated cytokine production, and activation of complement pathways (2-5). Initially, microglia respond to and surround plaques, degrading Aβ by phagocytosis (for review, see refs. 6-8). However, chronic activation of these cells shift microglia to a more proinflammatory and less phagocytic state (9, 10). Although much of the data implicating microglia in AD has come from neuropathological investigation, recent genome-wide association studies have provided the first genetic evidence (to our knowledge) linking microglia dysfunction to AD, with the discovery of risk polymorphisms in several immune system genes: CR1, TREM2, CD33, HLA-DRB5, MS4A6A, and ABCA7 (8,(11)(12)(13)(14)(15).In contrast to the field's increasing understanding of the role of innate immunity in AD, comparatively little is known about whether the adaptive immune system might also influence AD. Those studies that have examined these peripheral populations have largely focused on questions about their potential as biomarkers or their role in active Aβ immunization (3, 16). However, the adaptive and innate immune systems rarely fu...

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Section: Discussionsupporting

confidence: 66%

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

318

257

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“…The hope is to get satisfactory results from clinical studies with compounds that have been successful in vitro, ex vivo, and/or in vivo experiments, such as the administration of molecules like acetylpuerarin,138 edaravone,139 palmitoylethanolamide,38 N -[2-(4-hydroxyphenyl)ethyl]-2-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-hydroxyphenyl) acrylamide (compound FLZ),140 oleuropeinaglycone,141 oridonin,142 protocatechuic acid,143 resveratrol,110 rutin,144 or immunotherapies145,146 and vaccinations 147…”

Section: Future Research Directionmentioning

confidence: 99%

Targeting neuroinflammation in Alzheimer’s disease

Bronzuoli¹,

Iacomino²,

Steardo³

et al. 2016

JIR

207

150

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Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed every 3.2 seconds. Alzheimer’s disease (AD) accounts for approximately 60%–80% of all dementia cases. Given this evidence, it is clear dementia represents one of the greatest global public health challenges. Currently used drugs alleviate the symptoms of AD but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and tau tangles, new therapeutic approaches have other targets. One of the newest and most promising strategies is the control of reactive gliosis, a multicellular response to brain injury. This phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore their physiological functions and control the neuroinflammatory process offer new therapeutic opportunities for this devastating disease. In this review, we describe the role of neuroinflammation in the AD pathogenesis and progression and then provide an overview of the recent research with the aim of developing new therapies to treat this disorder.

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“…In agreement with this, repeated replacements of plasma by Aβ-free serum albumin (Albutein ® ) ameliorated cognitive decline in AD patients [35], which is consistent with the idea that albumin plays an important role in Aβ clearance and disposal. It should be mentioned that other serum proteins such as immunoglobulins (IVIG) have also shown to perform a protective role on preventing oxidative damage associated to AD [54, 55]. …”

Section: Discussionmentioning

confidence: 99%

Aberrant Co-localization of Synaptic Proteins Promoted by Alzheimer’s Disease Amyloid-β Peptides: Protective Effect of Human Serum Albumin

Domínguez-Prieto

Velasco

Vega

et al. 2016

JAD

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Amyloid-β (Aβ), Aβ40, Aβ42, and, recently, Aβ25-35 have been directly implicated in the pathogenesis of Alzheimer’s disease. We have studied the effects of Aβ on neuronal death, reactive oxygen species (ROS) production, and synaptic assembling in neurons in primary culture. Aβ25-35, Aβ40, and Aβ42 significantly decreased neuronal viability, although Aβ25-35 showed a higher effect. Aβ25-35 showed a more penetrating ability to reach mitochondria while Aβ40 did not enter the neuronal cytosol and Aβ42 was scarcely internalized. We did not observe a direct correlation between ROS production and cell death because both Aβ40 and Aβ42 decreased neuronal viability but Aβ40 did not change ROS production. Rather, ROS production seems to correlate with the penetrating ability of each Aβ. No significant differences were found between Aβ40 and Aβ42 regarding the extent of the deleterious effects of both peptides on neuronal viability or synaptophysin expression. However, Aβ40 elicited a clear delocalization of PSD-95 and synaptotagmin from prospective synapsis to the neuronal soma, suggesting the occurrence of a crucial effect of Aβ40 on synaptic disassembling. The formation of Aβ40- or Aβ42-serum albumin complexes avoided the effects of these peptides on neuronal viability, synaptophysin expression, and PSD-95/synaptotagmin disarrangement suggesting that sequestration of Aβ by albumin prevents deleterious effects of these peptides. We can conclude that Aβ borne by albumin can be safely transported through body fluids, a fact that may be compulsory for Aβ disposal by peripheral tissues.

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Intravenous Immunoglobulin (IVIG) Treatment Exerts Antioxidant and Neuropreservatory Effects in Preclinical Models of Alzheimer’s Disease

Cited by 19 publications

References 25 publications

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Targeting neuroinflammation in Alzheimer’s disease

Aberrant Co-localization of Synaptic Proteins Promoted by Alzheimer’s Disease Amyloid-β Peptides: Protective Effect of Human Serum Albumin

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Intravenous Immunoglobulin (IVIG) Treatment Exerts Antioxidant and Neuropreservatory Effects in Preclinical Models of Alzheimer’s Disease

Cited by 19 publications

References 25 publications

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Targeting neuroinflammation in Alzheimer&rsquo;s disease

Aberrant Co-localization of Synaptic Proteins Promoted by Alzheimer’s Disease Amyloid-β Peptides: Protective Effect of Human Serum Albumin

Contact Info

Product

Resources

About

Targeting neuroinflammation in Alzheimer’s disease