ABSTRACT
The N-terminally truncated pyroglutamate Aß3-42 (AßpE3-42) and Aß4-42 peptides are known to be highly abundant in the brain of Alzheimer's disease (AD) patients. Both peptides show enhanced aggregation and neurotoxicity in comparison to full-length Aß, suggesting that these amyloid peptides may play an important role in the pathogenesis of AD. The aim of the present work was to study the direct effect of the combination of AßpE3-42 and Aß4-42 on ongoing AD-related neuron loss, pathology, and neurological deficits in transgenic mice. Bigenic mice were generated by crossing the established TBA42 and Tg4-42 mouse models expressing the N-truncated Aß peptides AßpE3-42 and Aß4-42, respectively. After generation of the bigenic mice, detailed phenotypical characterization was performed using either immunostainings to evaluate amyloid pathology or quantification of neuron numbers using design-based stereology. The elevated plus maze was used to study anxiety levels. In order to evaluate sensori-motor deficits, the inverted grid, the balance beam and the string suspension tasks were applied. We could demonstrate that co-expression of AßpE3-42 and Aß4-42 accelerates neuron loss in the CA1 pyramidal layer of young bigenic mice as seen by reduced neuron numbers in comparison to single transgenic homozygous mice expressing either AßpE3-42 or Aß4-42. This observation coincides with the robust intraneuronal Aß accumulation observed in the bigenic mice. In addition, loss of anxiety and motor deficits were enhanced in an age-dependent manner. The sensori-motor deficits correlate with the abundant spinal cord pathology, as demonstrated by robust intracellular Aß accumulation within motor neurons and extracellular Aß deposition. Our observations demonstrate that a combination of AßpE3-42 and Aß4-42 has a stronger effect on ongoing AD pathology than the peptides alone. Therefore, AßpE3-42 and Aß4-42 might represent excellent potential therapeutic targets and diagnostic markers for AD.
