Abstract
The N-terminally truncated pyroglutamate Aβ3−42 (AβpE3−42) and Aβ4−42 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 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 AβpE3−42 and Aβ4−42 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 Aβ peptides AβpE3−42 and Aβ4−42, 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 AβpE3−42 and Aβ4−42 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 AβpE3−42 or Aβ4−42. 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 AβpE3−42 and Aβ4−42 has a stronger effect on ongoing AD pathology than the peptides alone. Therefore, AβpE3−42 and Aβ4−42 might represent excellent potential therapeutic targets and diagnostic markers for AD.
Highlights
Alzheimer’s disease (AD) is the most common type of dementia worldwide
In young TBA42hem (246,145 ± 6,280), TBA42hom (223,937 ± 14,553), and Tg4-42hem (245,925 ± 15,234) mice no significant neuron loss could be detected when compared to age-matched WT mice, while Tg442hom mice showed already a 20% neuron loss compared to WT (p < 0.01, 208,057 ± 10,452)
It was discovered that more than 60% of the amyloid-β protein (Aβ) peptides purified from the amyloid plaque cores of AD brains started with Phenylalanine at position 4 of the Aβ sequence (Masters et al, 1985)
Summary
Alzheimer’s disease (AD) is the most common type of dementia worldwide. Pathologically, AD represents a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β protein (Aβ), neurofibrillary tangles comprising hyperphosphorylated Tau, and neuronal loss. Regardless of the C-terminus of Aβ (Aβ40 or Aβ42), pyroglutaminylated isoforms at position 3 revealed an increased neurotoxicity and higher resistance to degradation than fulllength Aβ peptides (Russo et al, 2002; Schlenzig et al, 2009) In accordance with these observations, we have observed that AβpE3−42 and Aβ4−42 are rapidly converted into soluble toxic aggregates in vitro and this propensity to form aggregates is more pronounced than N-terminally intact Aβ1−42 (Bouter et al, 2013). The TBA42 mouse model solely expresses AβpE3−42 (Glu-3 mutated to Gln-3 in order to facilitate pyroGlu-3 formation) and develops intraneuronal Aβ accumulation, massive pyramidal neuron loss in the CA1 region of the hippocampus, motor impairment and behavioral deficits (Wittnam et al, 2012; Meißner et al, 2015). The aim of this work was to study a possible effect of AβpE3−42 and Aβ4−42 expression on neuron loss, pathology and neurological deficits in transgenic mice
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