Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse

Schenk, Dale; Barbour, Robin; Dunn, Whitney; Gordon, Grace; Grajeda, Henry; Guido, Teresa; Hu, Kang; Huang, Jiping; Johnson-Wood, Kelly; Khan, Karen; Kholodenko, Dora; Lee, Mike; Liao, Ziyuan; Lieberburg, Ivan; Motter, Ruth; Mutter, Linda; Soriano, Ferdie; Shopp, George M.; Vasquez, Nicki; Vandevert, Christopher; Walker, Shannan; Wogulis, Mark; Yednock, Ted; Games, Dora; Seubert, Peter

doi:10.1038/22124

Cited by 2,977 publications

(2,043 citation statements)

References 16 publications

(14 reference statements)

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“…AN-1792 was the first active immunotherapy strategy for AD. In PDAPP mice (overexpressing a disease-related mutant APP), immunization prevented and rescued the AD behavioral and pathological phenotypes [13]. The multinational phase 2a trial in people with mild-to-moderate AD was suspended when 6 % of patients had a side effect, including 4 with aseptic meningoencephalitis [14].…”

Section: Clinical Trial Setbacks For Drugs That Target Aβmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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Section: Clinical Trial Setbacks For Drugs That Target Aβmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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“…Therefore, transgenic models of Aβ pathology have been developed that overexpress human APP (hAPP) with AD‐associated mutations which favour the amyloidogenic β‐secretase pathway of APP processing (Games et al ., 1995; Hsiao et al ., 1996; Sturchler‐Pierrat et al ., 1997). These mice have been used to test therapeutic strategies that aim at reducing Aβ generation, for example by treatment with β‐secretase inhibitors and by active and passive immunization approaches (Solomon et al ., 1996; Schenk et al ., 1999; Eketjall et al ., 2013). Interestingly, transgenic mice overexpressing hAPP without AD‐related mutations, like I5, barely develop any Aβ deposits at high age (Mucke et al ., 2000).…”

Section: Introductionmentioning

confidence: 99%

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

et al. 2016

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SummaryAlzheimer's disease (AD) is histopathologically characterized by neurodegeneration, the formation of intracellular neurofibrillary tangles and extracellular Aβ deposits that derive from proteolytic processing of the amyloid precursor protein (APP). As rodents do not normally develop Aβ pathology, various transgenic animal models of AD were designed to overexpress human APP with mutations favouring its amyloidogenic processing. However, these mouse models display tremendous differences in the spatial and temporal appearance of Aβ deposits, synaptic dysfunction, neurodegeneration and the manifestation of learning deficits which may be caused by age‐related and brain region‐specific differences in APP transgene levels. Consequentially, a comparative temporal and regional analysis of the pathological effects of Aβ in mouse brains is difficult complicating the validation of therapeutic AD treatment strategies in different mouse models. To date, no antibodies are available that properly discriminate endogenous rodent and transgenic human APP in brains of APP‐transgenic animals. Here, we developed and characterized rat monoclonal antibodies by immunohistochemistry and Western blot that detect human but not murine APP in brains of three APP‐transgenic mouse and one APP‐transgenic rat model. We observed remarkable differences in expression levels and brain region‐specific expression of human APP among the investigated transgenic mouse lines. This may explain the differences between APP‐transgenic models mentioned above. Furthermore, we provide compelling evidence that our new antibodies specifically detect endogenous human APP in immunocytochemistry, FACS and immunoprecipitation. Hence, we propose these antibodies as standard tool for monitoring expression of endogenous or transfected APP in human cells and APP expression in transgenic animals.

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“…The initial attempts to immunize mice transgenic for human mutant APP genes with the amyloidogenic fragment were startlingly successful, with impressive plaque resolution. 99 The results were significant enough to result in a clinical trial. Unfortunately, perhaps predictably, about 5% of the immunized individuals developed severe inflammatory disease of the central nervous system.…”

Section: Interfaces Between the Amyloidoses And The Immune Systemmentioning

confidence: 95%

The genetics of the amyloidoses: interactions with immunity and inflammation

Buxbaum

2006

Genes Immun

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Historically, the amyloidoses have been associated with inflammation and the immune response. From Virchow's original description in human pathologic inflammatory states through their identification in horses used to produce antitoxin to their frequent occurrence in the course of multiple myeloma and a somewhat abortive designation as 'gammaloid', the disorders were felt to have an inflammatory origin. These presumptive associations antedated the availability of a reliable method for tissue extraction that would allow chemical analysis of the major deposited molecules. With the identification of the multiple precursors and the realization that most were not intrinsic elements of immune/inflammatory pathways, the investigative emphasis shifted to the analysis of the biophysical events involved in aggregation and fibril formation. As more in vivo models and better tools for examination of tissues have become available, it appears as if inflammation may participate as both a response to, and an amplifier of, the effects of the fibrillar aggregates. Hence, while only a limited number of amyloid protein precursors are involved in immunity and inflammation per se, host defense, in its broadest sense, is likely to be involved in the clinically relevant amyloidoses. Further it now appears that harnessing the immune respone in an appropriate fashion may be able to play a role in treatment.

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Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse

Cited by 2,977 publications

References 16 publications

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

The genetics of the amyloidoses: interactions with immunity and inflammation

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