Transnasal delivery of human A-beta peptides elicits impaired learning and memory performance in wild type mice

Abstract

BackgroundMurine models of Alzheimer’s disease (AD) are mainly based on overexpression of pathologic amyloid precursor protein and/or presenilins. Those genes resemble underlying cause of early onset type of AD while about 99 % of all human cases are to be characterized as sporadic, late onset. Appropriate animal models for this type of AD are still missing. We here investigated, if transnasal delivery of A-beta 42 peptides might serve to mimic pathological effects in mice.ResultsA-beta 42 peptides, used for the behavioral study, showed the expected dose-dependent toxicity in neur oblastoma cell line SH-SY5Y and were able to form higher molecular weight species in vitro. Upon delivery into nostrils of wild type mice, protein bands that might represent aggregation products of the exogenously applied human A-beta 42 were only observed in total brain homogenates from mice pre-treated with mannitol. By using TAMRA-labeled A-beta 42 peptides we demonstrated, that transport throughout the brain was achieved already 1 h after administration. FVB/N mice treated with A-beta 42 for 3 days were significantly impaired in the cue-retention condition of the fear conditioning task as compared to controls whereas A-beta-treated C57B6/J mice were impaired in the context condition. In the Morris water maze test, these mice also displayed a delayed learning performance, indicated by significantly longer time to find the platform. Those deficits were also seen for memory performance in the probe trial as measured by number of crossings of the former platform position and time spent in the goal quadrant.ConclusionsExisting AD mouse models are of genetic origin and need prolonged housing time before onset of pathology. Our short-term treatment induced learning and memory deficits via exogenous application of A-beta peptides comparable to those observed for the transgenic animals. With the transnasal A-beta 42 treatment we present an approach to investigate purely A-beta related changes suitable as a model for symptoms of Alzheimer’s dementia (AD). Resulting behavioral deficits were indicative for familial type of Alzheimer’s disease as well as for the late onset variant.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0280-9) contains supplementary material, which is available to authorized users.

Alzheimer's disease in the gut—Major changes in the gut of 5xFAD model mice with ApoA1 as potential key player

“…To further illuminate the role of ApoA1 in AD‐like pathology, the potential effect of ApoA1 on typical pathological processes was investigated. A‐beta monomers have been shown to be neurotoxic 49 . They are the predominant amyloid species synthesized by neurons 50 and since between monomeric and oligomeric A‐beta there was no difference observed in modulating ApoA1 expression, all further experiments were conducted with monomeric A‐beta.…”

“…A-beta monomers have been shown to be neurotoxic. 49 They are the predominant amyloid species synthesized by neurons 50 and since between monomeric and oligomeric A-beta there was no difference observed in modulating ApoA1 expression, all further experiments were conducted with monomeric A-beta. To demonstrate that ApoA1 possesses the property to bind A-beta peptides and modulate A-beta aggregation, ApoA1 and A-beta were co-incubated and aggregation products analyzed on a native PAA-gel.…”

Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer’s disease hallmarks

“…For measuring a potential protective effect of disulfiram on A-beta treatment of cells, SH-SY5Y cells were seeded at a density of 38 000 cells per well of a 96 well plate (Greiner Bio-OneGmbH, Frickenhausen, Germany) in culture medium supplemented with solvent (DMSO), human A-beta 42 peptides (2.5 µM, Anaspec) or peptides combined with 2.2 µM disulfiram for 48 h. Subsequently, MTT reagent was added (5 µl of 5 mg/ml stock solution) and viability assessed as described before 56 .…”

“…IHC sections were prepared and stained with anti-APP antibody 6E10 (Covance) as described previously 56 . Two sections per mouse were used for densitometric analysis in a total magnification of 40 × : five areas were determined to be measured as shown in Fig.…”

Amyloidogenic Peptides in Human Neuro-Degenerative Diseases and in Microorganisms: A Sorrow Shared Is a Sorrow Halved?

“…Besides the vagus nerve, also other tissues might be implicated in further progression of amyloid spreading such as the olfactory epithelium, the mucosa of the oral cavity and the trigeminal nerve. Administering fluorescent amyloid-β peptides e.g., to the nostrils of mice after mannitol-based relaxation of the blood-brain-barrier led already after 1 h to signals in tissue homogenates derived from the hippocampus and cortical regions [89]. Moreover, this was accompanied by impaired learning and memory performance as measured by fear conditioning and Morris water maze task.…”