Dataset Information

Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model.

ABSTRACT: Alzheimer's disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APP(SL)PS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human beta-amyloid (Abeta) precursor protein. Abeta(x-42) is the major form of Abeta species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain. At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Abeta and thioflavine-S-positive intracellular material but not with extracellular Abeta deposits. A strong reactive astrogliosis develops together with the neuronal loss. This loss is already detectable at 6 months of age and is PS1KI gene dosage-dependent. Thus, APP(SL)PS1KI mice further confirm the critical role of intraneuronal Abeta(42) in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.

SUBMITTER: Casas C

PROVIDER: S-EPMC1618627 | biostudies-literature | 2004 Oct

REPOSITORIES: biostudies-literature

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Publications

Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model.

Casas Caty C Sergeant Nicolas N Itier Jean-Michel JM Blanchard Véronique V Wirths Oliver O van der Kolk Nicolien N Vingtdeux Valérie V van de Steeg Evita E Ret Gwenaëlle G Canton Thierry T Drobecq Hervé H Clark Allan A Bonici Bruno B Delacourte André A Benavides Jesús J Schmitz Christoph C Tremp Günter G Bayer Thomas A TA Benoit Patrick P Pradier Laurent L

The American journal of pathology 20041001 4

Alzheimer's disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APP(SL)PS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human beta-amyloid (Abeta) precursor pr ...[more]

PMID: 15466394

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Project description:BackgroundThe amyloid hypothesis in Alzheimer disease (AD) considers amyloid ? peptide (A?) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated A? peptides especially N-truncated pyroglutamate A?pE3-42 have been extensively studied. Together with full-length A?1-42 and A?1-40, N-truncated A?pE3-42 and A?4-42 are major variants in AD brain. Although A?4-42 has been known for a much longer time, there is a lack of studies addressing the question whether A?pE3-42 or A?4-42 may precede the other in Alzheimer's disease pathology.ResultsUsing different A? antibodies specific for the different N-termini of N-truncated A?, we discovered that A?4-x preceded A?pE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel A?4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated A? species. While NT4X-167 significantly rescued A?4-42 toxicity in vitro no beneficial effect was observed against A?1-42 or A?pE3-42 toxicity. Phenylalanine at position four of A? was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1?9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD.ConclusionsA?4-x precedes A?pE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with A?4-x and represents a novel tool in Alzheimer research.

Dataset Information

Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model.

Publications

Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model.

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