Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated Aβ Is Induced by Pyroglutamate–Aβ Formation

Abstract

Posttranslational amyloid-␤ (A␤) modification is considered to play an important role in Alzheimer's disease (AD)etiology. An N-terminally modified A␤ species, pyroglutamate-amyloid-␤ (pE3-A␤), has been described as a major constituent of A␤ deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated A␤ species by glutaminyl cyclase (QC; QPCT) and/or its isoenzyme (isoQC; QPCTL), pE3-A␤ aggregates rapidly and is known to seed additional A␤ aggregation. To directly investigate pE3-A␤ toxicity in vivo, we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human A␤. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating A␤ and pE3-A␤ deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3-A␤ neurotoxicity, this phenotype was not found in heterozygous animals but in homozygous TBA2.1 or double-heterozygous TBA2.1/2.2 animals only. A significant amount of pE3-A␤ formation was shown to be QC-dependent, because crossbreeding of TBA2.1 with QC knock-out, but not isoQC knock-out, mice significantly reduced pE3-A␤ levels. Hence, lowering the rate of QC-dependent posttranslational pE3-A␤ formation can, in turn, lower the amount of neurotoxic A␤ species in AD.

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Two key observations support this theory: 1) familial AD mutations in APP elevate the expression of Aβ1-42 [24,25]; and 2) Aβ1-42 is more prone to aggregation and is more toxic than Aβ1-40 [26,27]. However, it was reported that pyroglutamate-Aβ, which is also presented in AD plaques, could also be the toxic isoform of Aβ [28][29][30][31]. Pyroglutamate-Aβ is more prone to aggregation compared with Aβ1-42 [29].…”

“…Pyroglutamate-Aβ is more prone to aggregation compared with Aβ1-42 [29]. Mice overexpressing this peptide showed a selective hippocampal neurodegeneration [31], and passive immunization against this peptide reduces the amyloid burden in an APP/PS1 double-transgenic mouse model [30]. In addition, Aβ1-43, generated by a disease-related PS1 mutant, was recently profiled as an overlooked neurotoxic isoform as this species was shown to have a higher propensity to aggregate and was more toxic than Aβ1-42 [32].…”

Altered neurogenesis in mouse models of Alzheimer disease

“…Surprisingly, no beneficial effects on working memory, extracellular Ab plaque load, neuron loss, as well as hippocampal neurogenesis could be detected. 25 A direct link between intraneuronal Ab accumulation and subsequent neuron loss in distinct brain regions has been also established in mouse models like TBA2.1 34 or Tg4-42, 35 engineered to directly overexpress mutant Ab peptides in the absence of mutant APP overexpression. These models use the neuronspecific Thy1-promotor to overexpress the N-terminal truncated Ab species Ab3-42 or Ab4-42 and are characterized by extensive CA1 neuron loss and associated behavioral deficits.…”

“…These models use the neuronspecific Thy1-promotor to overexpress the N-terminal truncated Ab species Ab3-42 or Ab4-42 and are characterized by extensive CA1 neuron loss and associated behavioral deficits. [34][35][36] In the Tg4-42 model, enhanced physical activity using enriched housing in cages equipped with running wheels resulted in an amelioration of CA1 neuron loss, accompanied by a significantly increased overall dentate gyrus granule cell number and a concomitant increase in the number of DCX-positive cells in the DG. 26 So far, no accumulation of Ab peptides within dentate gyrus neurons has been reported in any of the mouse models that have been studied.…”

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…In the AD brain, QC activity and pE-Aß levels are increased by several folds and distinct types of pE-Aß deposits, where pE3-Aß(3-42) predominates, have been identified at sites of QC-immunoreactive neurons and in target fields of QC-rich projection neurons . Chronic pharmacologic inhibition of QC or suppression of its encoding gene (Alexandru et al, 2011;Wirths et al, 2009) in transgenic mouse models of AD resulted in reduced pE-Aß peptide generation and improved performance in cognitive tasks, whereas QC overexpression worsened neuropathology and cognitive dysfunction (Jawhar et al, 2011b).…”