Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model

Abstract

It is well established that only a fraction of Ab peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (Ab 1D ) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Ab starting at position 3 and ending with amino acid 42 [Ab 3(pE)-42 ] have been previously shown to represent a major species in the brain of AD patients. When compared with Ab 1-42 , this peptide has stronger aggregation propensity and increased toxicity in vitro. Although it is unknown which peptidases remove the first two N-terminal amino acids, the cyclization of Ab at N-terminal glutamate can be catalyzed in vitro. Here, we show that Ab 3(pE)-42 induces neurodegeneration and concomitant neurological deficits in a novel mouse model (TBA2 transgenic mice). Although TBA2 transgenic mice exhibit a strong neuronal expression of Ab 3-42 predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Ab 3(pE)-42 in TBA2 mice were comparable to the APP/PS1KI mouse model with robust neuron loss and associated behavioral deficits. Eight weeks after birth TBA2 mice developed massive neurological impairments together with abundant loss of Purkinje cells. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Ab 3(pE)-42 is neurotoxic in vivo.

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

“…We could demonstrate that A␤ pE3-42 induces age-dependent behavioral deficits in TBA42 mice. This finding is consistent with previous studies in similar transgenic models expressing A␤ pE3-42 (19,20). Transgenic expression of hQC in 5XFAD mice also leads to the elevation of A␤ pE3 , thereby exacerbating behavioral deficits, increasing plaque load, and raising levels of A␤ pE3-42 but not general A␤ x-42 .…”

“…Taken together, these findings suggest that truncated and modified A␤ peptides have an important implication for neurodegeneration in murine models of AD. The TBA42 mouse model, like the previously published TBA2, TBA2.1, and TBA2.2 models (19,20), expresses A␤ 3Q-42 starting with an N-terminal glutamine (Gln) residue at position three of A␤. Glutamine was used instead of the naturally occurring glutamate because it is a better substrate for Motor function and anxiety were assessed in 6-month-old WT, 5XFAD, TBA42, and FAD42 mice using the balance beam (A) and elevated plus maze (B), respectively.…”

“…Transgenic Mice-The generation of the transgenic vector expressing murine thyrotropin-releasing hormone-A␤ (mTRH-A␤ ) under the control of the murine Thy1.2 regulatory sequence was described previously (17,19,20). The glutamate at position three of the A␤ amino acid sequence was mutated into glutamine to facilitate enhanced pyroglutamate formation.…”

“…Experiments involving various mouse models have highlighted the toxicity of A␤ pE3 . Overexpression of A␤ pE3-42 in the brains of transgenic mice triggers neuron loss and an associated neurological phenotype (19,20). Blocking QC function, either through genetic knock-out (21) or pharmacological inhibition (22), lowers A␤ pE3 levels, decreases plaque load, and ameliorates behavioral deficits in different AD mouse models.…”

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).…”