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 Abeta peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (Abeta(1D)) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Abeta starting at position 3 and ending with amino acid 42 [Abeta(3(pE)-42)] have been previously shown to represent a major species in the brain of AD patients. When compared with Abeta(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 Abeta at N-terminal glutamate can be catalyzed in vitro. Here, we show that Abeta(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 Abeta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Abeta(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 Abeta(3(pE)-42) is neurotoxic in vivo.
Wirths
Oliver
O
Division of Molecular Psychiatry, Department of Psychiatry, University of Goettingen, Von-Siebold-Strasse 5, Goettingen, Germany.
Breyhan
Henning
H
Cynis
Holger
H
Schilling
Stephan
S
Demuth
Hans-Ulrich
HU
Bayer
Thomas A
TA
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C532271:amyloid beta-protein (3-42), pyroglutamyl(3)-