Oligomeric Pyroglutamate Amyloid-β is Present in Microglia and a Subfraction of Vessels in Patients with Alzheimer's Disease: Implications for Immunotherapy

Wirths, Oliver; Hillmann, Antje; Pradier, Laurent; Härtig, Wolfgang; Bayer, Thomas A.

doi:10.3233/jad-121945

Cited by 21 publications

(14 citation statements)

References 41 publications

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“…Consistent with such a mechanism, they observed that treatment with 3D6 led to increased microglial colocalization with amyloid deposits in vivo. We have also observed that pyroGlu-3 peptides can be observed in microglia in the APP/PS1KI mouse model as an indication of phagocytotic activity [109]. …”

Section: N-truncated Aβ As a Target For Immunotherapymentioning

confidence: 99%

Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease

2014

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Although N-truncated Aβ variants are known to be the main constituent of amyloid plaques in the brains of patients with Alzheimer’s disease, their potential as targets for pharmacological intervention has only recently been investigated. In the last few years, the Alzheimer field has experienced a paradigm shift with the ever increasing understanding that targeting amyloid plaques has not led to a successful immunotherapy. On the other hand, there can be no doubt that the amyloid cascade hypothesis is central to the etiology of Alzheimer’s disease, raising the question as to why it is apparently failing to translate into the clinic. In this review, we aim to refocus the amyloid hypothesis integrating N-truncated Aβ peptides based on mounting evidence that they may represent better targets than full-length Aβ. In addition to Aβ peptides starting with an Asp at position 1, a variety of different N-truncated Aβ peptides have been identified starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10 and pyroglutamylated Glu-11. Certain forms of N-truncated species are better correlates for early pathological changes found pre-symptomatically more often than others. There is also evidence that, together with full-length Aβ, they might be physiologically detectable and are naturally secreted by neurons. Others are known to form soluble aggregates, which have neurotoxic properties in transgenic mouse models. It has been clearly demonstrated by several groups that some N-truncated Aβs dominate full-length Aβ in the brains of Alzheimer’s patients. We try to address which of the N-truncated variants may be promising therapeutic targets and which enzymes might be involved in the generation of these peptides

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Section: N-truncated Aβ As a Target For Immunotherapymentioning

confidence: 99%

Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease

2014

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“…A 500 mg dose of the antibody resulted in improvement in acquisition learning in the water T-maze test in A␤PPswe/PS1dE9 transgenic mice. Note that oligomeric pyroglutamate A␤ is present in microglia and a subfraction of vessels in patients with AD, which has implications for immunotherapy [665] (Thomson Reuters Pharma, update of December 23, 2013).…”

Section: Antibodies Against Amyloid-βmentioning

confidence: 99%

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

Froestl

Pfeifer

Muhs

2014

JAD

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Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

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“…It has been shown that the main component of senile plaques from AD patients is pE –Aβs, especially pE−Aβ 3‐40/42. In addition, some studies suggested that pGlu‐Aβ is critical to the development of AD, especially in the early stage . Therefore, QC represents an attractive target to develop novel treatments for AD .…”

Section: Introductionmentioning

confidence: 99%

The Development of Small Molecule Inhibitors of Glutaminyl Cyclase and Isoglutaminyl Cyclase for Alzheimer's Disease

et al. 2019

ChemistrySelect

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Alzheimer's disease (AD), a common form of dementia, is a progressive neurodegenerative disease and one of the leading causes of death in the elderly worldwide. The exact underlying pathogenesis of AD remains elusive because of its complexity and involvement of multiple factors. Glutaminyl cyclase (QC) and isoGlutaminyl cyclase (isoQC) belong to the family of the metalloenzymes and catalyze the intramolecular cyclization of N-terminal L-glutamine/glutamate residues of certain proteins into pyroglutamic acid (pGlu). The amyloid protein and the monocyte chemoattractant protein (MCP-1) also known as CCL2 that promotes a cascade of inflammation-related responses are two representative substrates. Moreover, it has been demonstrated that the pyroglutamated Aβ and CCL2 exhibit more severe neurotoxicity than normal Aβ and CCL2. Thus, QC represents one of the attractive targets to develop novel treatments for AD. In this review the recent development of QC inhibitors as anti-AD agents will be summarized.

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Oligomeric Pyroglutamate Amyloid-β is Present in Microglia and a Subfraction of Vessels in Patients with Alzheimer's Disease: Implications for Immunotherapy

Cited by 21 publications

References 41 publications

Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease

Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

The Development of Small Molecule Inhibitors of Glutaminyl Cyclase and Isoglutaminyl Cyclase for Alzheimer's Disease

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