Pathological Hallmarks, Clinical Parallels, and Value for Drug Testing in Alzheimer's Disease of the APP[V717I] London Transgenic Mouse Model - PubMed (original) (raw)

Pathological Hallmarks, Clinical Parallels, and Value for Drug Testing in Alzheimer's Disease of the APP[V717I] London Transgenic Mouse Model

An Tanghe et al. Int J Alzheimers Dis. 2010.

Abstract

The APP[V717I] London (APP-Ld) mouse model recapitulates important pathological and clinical hallmarks of Alzheimer's disease (AD) and is therefore a valuable paradigm for evaluating therapeutic candidates. Historically, both the parenchymal and vascular amyloid deposits, and more recently, truncated and pyroglutamate-modified Abeta(3(pE)-42) species, are perceived as important hallmarks of AD-pathology. Late stage symptoms are preceded by robust deficits in orientation and memory that correlate in time with Abeta oligomerization and GSK3β-mediated phosphorylation of endogenous murine Tau, all markers that have gained considerable interest during the last decade. Clinical parallels with AD patients and the value of the APP-Ld transgenic mouse model for preclinical in vivo testing of candidate drugs are discussed.

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Figures

Figure 1

Figure 1

Abeta aggregation prior to plaque formation in APP[V717I] (APP-Ld) and APP[V717I] × PS1[A246E] mice. (a) Representative photo collection of anti-Abeta stained sections showing total plaque load in APP-Ld mice of different ages (proprietary anti-Abeta Nanobody, reMYND/Ablynx, Belgium). (b) Aggregated Abeta in APP-Ld mice of different ages, both in preplaque (indicated by the dashed line) and postplaque stages of the Alzheimer pathology (A4-assay, Amorfix Life Sciences Ltd., Mississauga, Canada). The signal of nontransgenic mice was under the S/N cutoff value (data not shown). (c) As in B, for the APP[V717I] × PS1[A246E] model. The signal of nontransgenic mice was under the S/N cutoff value (data not shown).

Figure 2

Figure 2

Abeta3(pE)–42 determination in the SDS and FA extracts of APP-Ld brain. Pan-Abeta42 (a, b) and Abeta3(pE)–42 (c,d) concentrations in SDS (a, c) and FA (b, d), as well as the corresponding Abeta3(pE)–42 to pan-Abeta42 ratios (in %) (e, f).

Figure 3

Figure 3

Progression of CSF Abeta42/40 ratios in ageing APP-Ld mice; from the age of 15 months onwards, the ratio of Abeta42/40 in CSF decreases.

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