A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice.

• Amyloid-beta (Abeta) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Abeta is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Abeta in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Abeta was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Abeta plaques displayed a patchy morphology with bundles of Abeta fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Abeta was observed following acute administration of an Abeta antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Abeta efflux. TgAPP-ArcSwe, with its insoluble state of deposited Abeta, could serve as a complementary model to better predict the outcome of clinical trials.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Psykiatri (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Psychiatry (hsv//eng)

Nyckelord

Aged

Aged

80 and over

Alzheimer Disease

genetics

metabolism

physiopathology

Amyloid beta-Protein

antagonists & inhibitors

chemistry

metabolism

Amyloid beta-Protein Precursor

genetics

Animals

Antibodies

pharmacology

therapeutic use

Brain

metabolism

pathology

physiopathology

Disease Models

Animal

Genetic Predisposition to Disease

genetics

Humans

Mice

Mice

Transgenic

Microscopy

Electron

Transmission

Mutation

genetics

Senile Plaques

genetics

metabolism

pathology

Solubility

Immunotherapy

MEDICINE

Publikations- och innehållstyp

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