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

It is well established that only a fraction of Aβ peptides in the brain of Alzheimer’s disease (AD) patients start with N-terminal aspartate (Aβ(1D)) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Aβ starting at position 3 and ending with amino acid 42 [Aβ(3(pE)–42)] have been previously shown to represent a major species in the brain of AD patients. When compared with Aβ(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 Aβ at N-terminal glutamate can be catalyzed in vitro. Here, we show that Aβ(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 Aβ(3–42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Aβ(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 Aβ(3(pE)–42) is neurotoxic in vivo. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-009-0557-5) contains supplementary material, which is available to authorized users.