QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, July 2, 2008, 28(27):6787-6793; doi:10.1523/JNEUROSCI.2377-07.2008

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Schroeter, S. Articles by Games, D. Search for Related Content PubMed PubMed Citation Articles by Schroeter, S. Articles by Games, D.

 Previous Article  |  Next Article 

Neurobiology of Disease
Immunotherapy Reduces Vascular Amyloid-β in PDAPP Mice

Sally Schroeter,¹ Karen Khan,¹ Robin Barbour,¹ MinhTam Doan,¹ Ming Chen,¹ Terry Guido,¹ Davinder Gill,² Guriqbal Basi,¹ Dale Schenk,¹ Peter Seubert,¹ and Dora Games¹

¹Elan Pharmaceuticals, South San Francisco, California 94080, and ²Wyeth Pharmaceuticals, Cambridge, Massachusetts 02140

Correspondence should be addressed to Dora Games, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080. Email: dora.games{at}elan.com

In addition to parenchymal amyloid-β (Aβ) plaques, Alzheimer's disease (AD) is characterized by Aβ in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular Aβ (VAβ) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-Aβ antibodies may clear parenchymal amyloid but increase VAβ and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VAβ and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VAβ and microhemorrhage in PDAPP mice by comparing antibodies with different Aβ epitopes (3D6, Aβ_1–5; 266, Aβ_16–23) and performing a 3D6 dose–response study. VAβ and microhemorrhage were assessed using concomitant Aβ immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VAβ in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VAβ was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with Aβ deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VAβ levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VAβ. These observations raise the possibility that Aβ immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.

Key words: Aβ-peptide; Alzheimer's disease; antibody; chronic; transgenic; vascular

---

Received May 24, 2007; revised April 18, 2008; accepted May 12, 2008.

Correspondence should be addressed to Dora Games, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080. Email: dora.games{at}elan.com

Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2008 28: i. [Full Text]  

This article has been cited by other articles:

				B. Biscaro, O. Lindvall, C. Hock, C. T. Ekdahl, and R. M. Nitsch A{beta} Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice J. Neurosci., November 11, 2009; 29(45): 14108 - 14119. [Abstract] [Full Text] [PDF]

				M. Manczak, P. Mao, K. Nakamura, C. Bebbington, B. Park, and P. H. Reddy Neutralization of granulocyte macrophage colony-stimulating factor decreases amyloid beta 1-42 and suppresses microglial activity in a transgenic mouse model of Alzheimer's disease Hum. Mol. Genet., October 15, 2009; 18(20): 3876 - 3893. [Abstract] [Full Text] [PDF]

				D. M. Wilcock, N. Gharkholonarehe, W. E. Van Nostrand, J. Davis, M. P. Vitek, and C. A. Colton Amyloid Reduction by Amyloid-{beta} Vaccination Also Reduces Mouse Tau Pathology and Protects from Neuron Loss in Two Mouse Models of Alzheimer's Disease J. Neurosci., June 24, 2009; 29(25): 7957 - 7965. [Abstract] [Full Text] [PDF]

				J. Koenigsknecht-Talboo, M. Meyer-Luehmann, M. Parsadanian, M. Garcia-Alloza, M. B. Finn, B. T. Hyman, B. J. Bacskai, and D. M. Holtzman Rapid Microglial Response Around Amyloid Pathology after Systemic Anti-A{beta} Antibody Administration in PDAPP Mice J. Neurosci., December 24, 2008; 28(52): 14156 - 14164. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help