Targeting Beta Amyloid: A Clinical Review of Immunotherapeutic Approaches in Alzheimer's Disease

Lobello, Kasia; Ryan, Joanne; Liu, Enchi; Rippon, Gregory A.; Black, Ronald S.

doi:10.1155/2012/628070

Cited by 61 publications

(73 citation statements)

References 71 publications

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“…Other studies have demonstrated that Fc receptor interactions are not necessarily required for Aβ removal [52], suggesting that other mechanisms may also be involved in the Aβ clearance with active and passive immunotherapy. One of these proposed mechanisms of action is called peripheral sink, and thanks to this mechanism the formation of antigen-antibody complexes in the periphery allows the sequestration of amyloid away from the brain and prevents the deposition of new plaques.…”

Section: Harnessing the Immune System To Cure Ad: Vaccinationmentioning

confidence: 99%

Innate Immune System and Inflammation in Alzheimer's Disease: From Pathogenesis to Treatment

Serpente

Bonsi

Scarpini

et al. 2014

Neuroimmunomodulation

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Immune activation and inflammation, likely triggered by amyloid-beta (Aβ) deposition, play a remarkable role in the pathogenesis of Alzheimer's disease (AD), which is the most frequent cause of dementia in the elderly. The principal cellular elements of the brain innate immune system likely to be involved in such processes are microglia. In an attempt to search for new disease-modifying drugs, the immune system has been addressed, with the aim of removing deposition of Aβ or tau by developing vaccines and humanized monoclonal antibodies. The aim of this review is to summarize the current evidence regarding the role played by microglia and inflammatory molecules in the pathogenesis of AD. In addition, we will discuss the main active and passive immunotherapeutic approaches.

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Section: Harnessing the Immune System To Cure Ad: Vaccinationmentioning

confidence: 99%

Innate Immune System and Inflammation in Alzheimer's Disease: From Pathogenesis to Treatment

Serpente

Bonsi

Scarpini

et al. 2014

Neuroimmunomodulation

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show abstract

“…[21][22][23] Because immunotherapeutic strategies displayed great promise in animal models of AD, a strong effort was made by the industry to inhibit generation of toxic Ab aggregates and remove soluble and aggregated Ab deposited in the brains of AD patients by both active and passive anti-Ab immunotherapy strategies. [24][25][26][27][28][29][30][31] Data from active vaccine trials indicate that, to be effective, anti-Ab therapeutic should induce high titers of anti-Ab antibodies without activation of autoreactive T cells. [31][32][33][34] On the other hand, published results from both active and passive Ab-immunotherapy suggest that it should be initiated early in the disease, probably before toxic forms of this peptide accumulate in the brain.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

et al. 2017

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Previously, we reported that Alzheimer's disease (AD) epitope vaccines (EVs) composed of N-terminal b-amyloid (Ab 42 ) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Ab 42 is a target. Here, we directly compare the efficacy of anti-Ab 42 antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6-6.5 months for preventive vaccinations and 16-19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Ab antibodies, significantly reducing pathologic forms of Ab in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11-11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Ab antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance. INTRODUCTIONA critical goal of developing therapeutic interventions for Alzheimer's disease (AD) has been the identification of suitable targets. During the last two decades, the predominant theory of the etiology of AD was that Ab has a central role in the onset and progression of AD, as delineated in the amyloid cascade hypothesis. 1,2 According to this hypothesis, the accumulation of Ab peptide, either by overproduction or aberrant clearance, results in deposition of Ab in plaques, which leads to the formation of neurofibrillary tau tangles and cell death, resulting in dementia. Later on, the amyloid cascade hypothesis evolved to focus on oligomers and protofibrils of Ab as instigators in the destruction of synaptic function. [3][4][5] Support for the amyloid cascade hypothesis was spurred by the identification of mutations in amyloid precursor protein (APP) that are associated with familial AD 6-8 or protection against amyloid pathology and age-related Alzheimer's disease. [9][10][11] In addition, it was discovered that overexpression of APP due to trisomy 21 in Downs disease was associated with a high incidence of AD in these individuals. [12][13][14] Today it is clear that the pathological tau also plays a vital role in the development of AD pathology and progression of this disease, 15 correlating better with the degree of dementia than Ab plaques. Importantly, substantial data suggest that Ab pathology emerges many years prior to tau pathology and accelerates formation of toxic tau aggregates, [16][17][18] supporting the preventive rather than therapeutic potential of anti-amyloid therapies.Immunotherapies target...

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“…Although these studies, revealing vasogenic edema as a primary side effect, are quite discouraging in humans [8] they have shown therapeutic potential for sustainable clinical use. Given these results, we disagree on the "reason for optimism" in "preventive and symptomatic pharmacological intervention" as expressed by Lista et al [1].…”

mentioning

confidence: 99%

Hemodynamic changes in Alzheimer's disease: A leading role behind the courtain? Commentary on “CSF Aβ1‐42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer's disease” by Lista et al.

Diomedi

2014

Alzheimer's & Dementia

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Targeting Beta Amyloid: A Clinical Review of Immunotherapeutic Approaches in Alzheimer's Disease

Cited by 61 publications

References 71 publications

Innate Immune System and Inflammation in Alzheimer's Disease: From Pathogenesis to Treatment

Innate Immune System and Inflammation in Alzheimer's Disease: From Pathogenesis to Treatment

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

Hemodynamic changes in Alzheimer's disease: A leading role behind the courtain? Commentary on “CSF Aβ1‐42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer's disease” by Lista et al.

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