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N-truncated A?4-x peptides in sporadic Alzheimer's disease cases and transgenic Alzheimer mouse models.

ABSTRACT: The deposition of neurotoxic amyloid-? (A?) peptides in plaques in the brain parenchyma and in cerebral blood vessels is considered to be a key event in Alzheimer's disease (AD) pathogenesis. Although the presence and impact of full-length A? peptides such as A?1-40 and A?1-42 have been analyzed extensively, the deposition of N-terminally truncated A? peptide species has received much less attention, largely because of the lack of specific antibodies.This paper describes the generation and characterization of novel antibodies selective for A?4-x peptides and provides immunohistochemical evidence of A?4-x in the human brain and its distribution in the APP/PS1KI and 5XFAD transgenic mouse models.The A?4-x staining pattern was restricted mainly to amyloid plaque cores and cerebral amyloid angiopathy in AD and Down syndrome cases and in both AD mouse models. In contrast, diffuse amyloid deposits were largely negative for A?4-x immunoreactivity. No overt intraneuronal staining was observed.The findings of this study are consistent with previous reports demonstrating a high aggregation propensity of A?4-x peptides and suggest an important role of these N-truncated A? species in the process of amyloidogenesis and plaque core formation.

SUBMITTER: Wirths O

PROVIDER: S-EPMC5628465 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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N-truncated Aβ<sub>4-x</sub> peptides in sporadic Alzheimer's disease cases and transgenic Alzheimer mouse models.

Wirths Oliver O Walter Susanne S Kraus Inga I Klafki Hans W HW Stazi Martina M Oberstein Timo J TJ Ghiso Jorge J Wiltfang Jens J Bayer Thomas A TA Weggen Sascha S

Alzheimer's research & therapy 20171004 1

<h4>Background</h4>The deposition of neurotoxic amyloid-β (Aβ) peptides in plaques in the brain parenchyma and in cerebral blood vessels is considered to be a key event in Alzheimer's disease (AD) pathogenesis. Although the presence and impact of full-length Aβ peptides such as Aβ<sub>1-40</sub> and Aβ<sub>1-42</sub> have been analyzed extensively, the deposition of N-terminally truncated Aβ peptide species has received much less attention, largely because of the lack of specific antibodies.<h4> ...[more]

PMID: 28978359

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Project description:Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20-22 kDa NH2-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects.

Dataset Information

N-truncated A?4-x peptides in sporadic Alzheimer's disease cases and transgenic Alzheimer mouse models.

Publications

N-truncated Aβ<sub>4-x</sub> peptides in sporadic Alzheimer's disease cases and transgenic Alzheimer mouse models.

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