Author: Christian Clement ; Walter J. Lukiw ; Li Yuan Yuan ; Eli M. Kammerman ; James M. Hill ; Yuhai Zhao ; Jian Guo Cui ; Madelyn Corkern ; M. J. Ball ; Patrick M. Sullivan ; Partha S. Bhattacharjee

Human brains harbor herpes simplex virus type-1 (HSV-1) DNA, which normally remains quiescent throughout many decades of life. HSV-1 is associated with viral encephalopathy and with the amyloid beta 42 (Abeta42) peptide-enriched lesions that characterize Alzheimer's disease neuropathology. Here we report that infection of human neuronal-glial cells in primary co-culture with HSV-1 induces an irregular hypertrophy of human neuronal-glial cell bodies, an induction of HSV-1 DNA polymerase, and an up-regulation of micro-RNA-146a associated with altered innate-immune responses. Presence of the antiviral acyclovir or soluble Abeta42 peptide significantly attenuated these neuropathological responses. The inhibitory effects of Abeta42 peptide were also observed in an HSV-1-infected CV-1 cell-based viral plaque assay. The results suggest that soluble Abeta42 peptide can invoke non-pathological and anti-viral effects through inactivation of an HSV-1 challenge to human brain cells by simple viral sequestration, viral destruction, or by complex neurogenetic mechanisms.

26 Feb 2010·Journal of NeuroimmunologyQ3 · MEDICINE

Tetravalent Aβ1–15 vaccine reduces TCR-positive cell infiltration and up-regulates p75 in Tg2576 brains compared to Aβ42 vaccine

Q3 · MEDICINE

Article

Author: Jing Yu ; Juntao Zou ; Huaqiao Wang ; Jie Xu ; Zhibin Yao ; Hui Li

In order to investigate the effect of Abeta vaccines on T cell infiltration into the brain, we immunized Tg2576 mice with two adenovirus vaccines containing tetravalent Abeta1-15 (4xAbeta15) or Abeta42. TCR-positive cells were found in the ventricle, parenchyma, and surrounding the vasculature, especially concentrating in the periventricular parenchyma, the reticular part of the substantia nigra and the corpus striatum. Compared to the Abeta42 group, TCR-positive cells in the tetravalent (4x) Abeta15 group were significantly decreased. Both vaccines down-regulated neurotrophic and inflammatory factors, but the 4xAbeta15 vaccine up-regulated TrkA and p75 compared with the Abeta42 vaccine. The results suggest that the 4xAbeta15 vaccine might be safer and more beneficial than the Abeta42 vaccine.

28 Oct 2009·JAMAQ1 · MEDICINE

DNA β-Amyloid<sub>1-42</sub> Trimer Immunization for Alzheimer Disease in a Wild-Type Mouse Model

Q1 · MEDICINE

Article

Author: Olaf Stüve ; Bao Xi Qu ; Todd N. Eagar ; Min Fu ; Roger N. Rosenberg ; Doris Lambracht-Washington

CONTEXTDNA beta-amyloid(1-42) (Abeta42) trimer immunization was developed to produce specific T helper 2 cell (T(H)2)-type antibodies to provide an effective and safe therapy for Alzheimer disease (AD) by reducing elevated levels of Abeta42 peptide that occur in the brain of patients with AD.OBJECTIVETo compare the immune response in wild-type mice after immunization with DNA Abeta42 trimer and Abeta42 peptide.DESIGN AND INTERVENTIONWild-type mice received either 4 microg of DNA Abeta42 trimer immunization administered with gene gun (n = 8) or intraperitoneal injection of 100 microg of human Abeta42 peptide with the adjuvant Quil A (n = 8). Titers, epitope mapping, and isotypes of the Abeta42-specific antibodies were analyzed.MAIN OUTCOME MEASURESAntibody titers, mapping of binding sites (epitopes), isotype profiles of the Abeta42-specific antibodies, and T-cell activation.RESULTSDNA Abeta42 trimer immunization resulted in antibody titers with a mean of 15 microg per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a T(H)2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed T(H)1/T(H)2 immune response (IgG1/IgG2a ratio of 1) (P < .001). No increased T-cell proliferation was observed in the DNA-immunized mice (P = .03).CONCLUSIONIn this preliminary study in a wild-type mouse model, DNA Abeta42 trimer immunization protocol produced a T(H)2 immune response and appeared to have low potential to cause an inflammatory T-cell response.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 1	-	Eli Lilly & Co.	-

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