Synergistic Effect on Neurodegeneration by N-Truncated Aβ and Pyroglutamate Aβ in a Mouse Model of Alzheimer's Disease.

The N-terminally truncated pyroglutamate Aβ (Aβ) and Aβ 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 Aβ, 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 Aβ and Aβ 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 Aβ peptides Aβ and Aβ, 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 Aβ and Aβ 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 Aβ or Aβ. This observation coincides with the robust intraneuronal Aβ 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 Aβ accumulation within motor neurons and extracellular Aβ deposition. Our observations demonstrate that a combination of Aβ and Aβ has a stronger effect on ongoing AD pathology than the peptides alone. Therefore, Aβ and Aβ might represent excellent potential therapeutic targets and diagnostic markers for AD.