Identification of N-terminally truncated pyroglutamate amyloid-β in cholesterol-enriched diet-fed rabbit and AD brain.
The main amyloid-β peptide (Aβ) variants detected in the human brain are Aβ1-40 and Aβ1-42; however, a significant proportion of Aβ in Alzheimer's disease (AD) brain also consists of N-terminal truncated/modified species. AβN3(pE), Aβ peptide bearing amino-terminal pyroglutamate at position 3, has been demonstrated to be a major N-truncated/modified constituent of intracellular, extracellular, and vascular Aβ deposits in AD and Down syndrome brain tissue. It has been previously demonstrated that rabbits fed a diet enriched in cholesterol and given water containing trace copper levels developed AD-like pathology including intraneuronal and extracellular Aβ accumulation, tau hyperphosphorylation, vascular inflammation, astrocytosis, microgliosis, reduced levels of acetylcholine, as well as learning deficits and thus, may be used as a non-transgenic animal model of sporadic AD. In the present study, we have demonstrated for the first time the presence of AβN3(pE) in blood vessels in cholesterol-enriched diet-fed rabbit brain. In addition, we detected AβN3(pE) immunoreactivity in all postmortem AD brain samples studied. We believe that our results are potentially important for evaluation of novel therapeutic molecules/strategies targeting Aβ peptides in a suitable non-transgenic animal model.
Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Cuidad Universitaria, Mexico, DF, Mexico.
Roxanna
R
Perez-Garmendia
Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Cuidad Universitaria, Mexico, DF, Mexico.
Luis Fernando
LF
Hernandez-Zimbron
Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Cuidad Universitaria, Mexico, DF, Mexico.
Miguel Angel
MA
Morales
Brain Bank, National Laboratory of Experimental Services, CINVESTAV-IPN, Mexico, DF, Mexico.
José
J
Luna-Muñoz
Department of Neurosciences, CINVESTAV-IPN, Mexico, DF, Mexico.
Raul
R
Mena
Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Cuidad Universitaria, Mexico, DF, Mexico.
Miriam
M
Nava-Catorce
Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Cuidad Universitaria, Mexico, DF, Mexico.
Gonzalo
G
Acero
Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA.
Vitaly
V
Vasilevko
Brain Bank, National Laboratory of Experimental Services, CINVESTAV-IPN, Mexico, DF, Mexico.
Amparo
A
Viramontes-Pintos
Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA Department of Neurology, University of California Irvine, Irvine, CA, USA.
David H
DH
Cribbs
Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Cuidad Universitaria, Mexico, DF, Mexico.
Goar
G
Gevorkian
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011817:Rabbits
C000592483:A N11(pE) peptide; C000592482:A N3(pE) peptide; D016229:Amyloid beta-Peptides; D000906:Antibodies; D002791:Cholesterol, Dietary; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
Alzheimer's disease; amyloid-β; animal model; cholesterol-fed rabbit; pyroglutamate-modified amyloid