Passive Immunization against Pyroglutamate-3 Amyloid-β Reduces Plaque Burden in Alzheimer-Like Transgenic Mice: A Pilot Study

Background: N-terminally truncated and modified pyroglutamate-3 amyloid-β protein (pE3-Aβ) is present in most, if not all, cerebral plaque and vascular amyloid deposits in human Alzheimer’s disease (AD). pE3-Aβ deposition is also found in AD-like transgenic (tg) mouse brain, albeit in lesser quantities than general Aβ. pE3-Aβ resists degradation, is neurotoxic, and may act as a seed for Aβ aggregation. Objective: We sought to determine if pE3-Aβ removal by passive immunization with a highly specific monoclonal antibody (mAb) impacts pathogenesis in a mouse model of Alzheimer’s amyloidosis. Methods: APPswe/PS1ΔE9 tg mice were given weekly intraperitoneal injections of a new anti-pE3-Aβ mAb (mAb07/1) or PBS from 5.8 to 13.8 months of age (prevention) or from 23 to 24.7 months of age (therapeutic). Multiple forms of cerebral Aβ were quantified pathologically and biochemically. Gliosis and microhemorrhage were examined. Results: Chronic passive immunization with an anti-pE3-Aβ mAb significantly reduced total plaque deposition and appeared to lower gliosis in the hippocampus and cerebellum in both the prevention and therapeutic studies. Insoluble Aβ levels in hemibrain homogenates were not significantly different between immunized and control mice. Microhemorrhage was not observed with anti-pE3-Aβ immunotherapy. Conclusions: Selective removal of pE3-Aβ lowered general Aβ plaque deposition suggesting a pro-aggregation or seeding role for pE3-Aβ.

[1]  T. Bayer,et al.  Identification of low molecular weight pyroglutamate A{beta} oligomers in Alzheimer disease: a novel tool for therapy and diagnosis. , 2010, The Journal of biological chemistry.

[2]  T. Bayer,et al.  Identification of Low Molecular Weight Pyroglutamate Aβ Oligomers in Alzheimer Disease , 2010, The Journal of Biological Chemistry.

[3]  T. Bayer,et al.  Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease cases , 2009, Journal of Neural Transmission.

[4]  T. Bayer,et al.  Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model , 2009, Acta Neuropathologica.

[5]  Hans-Ulrich Demuth,et al.  Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer's disease–like pathology , 2008, Nature Medicine.

[6]  T. Saido,et al.  Amyloidogenic processing of amyloid precursor protein: evidence of a pivotal role of glutaminyl cyclase in generation of pyroglutamate-modified amyloid-beta. , 2008, Biochemistry.

[7]  G. Damonte,et al.  Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. , 2007, Archives of neurology.

[8]  B. Bohrmann,et al.  High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain , 2006, Neuroscience.

[9]  Brian J. Bacskai,et al.  Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease , 2006, Neurobiology of Disease.

[10]  Hans-Ulrich Demuth,et al.  On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). , 2006, Biochemistry.

[11]  A. Gliozzi,et al.  β-Amyloid Is Different in Normal Aging and in Alzheimer Disease* , 2005, Journal of Biological Chemistry.

[12]  B. Ghetti,et al.  Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques. , 2005, Biochemistry.

[13]  T. Hoffmann,et al.  Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions , 2004, FEBS letters.

[14]  Joanna L. Jankowsky,et al.  Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase , 2004 .

[15]  C. Lemere,et al.  Intranasal immunotherapy for the treatment of Alzheimer’s disease: Escherichia coli LT and LT(R192G) as mucosal adjuvants , 2002, Neurobiology of Aging.

[16]  D. Selkoe Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[17]  C. Barrow,et al.  The Aβ 3-Pyroglutamyl and 11-Pyroglutamyl Peptides Found in Senile Plaque Have Greater β-Sheet Forming and Aggregation Propensities in Vitro than Full-Length Aβ† , 1999 .

[18]  Kenneth S. Kosik,et al.  The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology , 1996, Nature Medicine.

[19]  T. Iwatsubo,et al.  Amino- and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain , 1996, Neuroscience Letters.

[20]  D. Selkoe,et al.  Sequence of Deposition of Heterogeneous Amyloid β-Peptides and APO E in Down Syndrome: Implications for Initial Events in Amyloid Plaque Formation , 1996, Neurobiology of Disease.

[21]  D. Mann,et al.  Dominant and differential deposition of distinct β-amyloid peptide species, Aβ N3(pE), in senile plaques , 1995, Neuron.

[22]  D. Borchelt,et al.  Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. , 2004, Human molecular genetics.