Alzheimer Disease: Obregon D

Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, Tan J. · Neuroimmunology Laboratory, Department of Psychiatry, Behavioral Medicine, Institute for Research in Psychiatry, University of South Florida, College of Medicine, Tampa, FL 33613, USA. · J Neuroinflammation. · Pubmed #19014446 links to  free full text

Abstract: Recently, the term "inflammaging" was coined by Franceshci and colleagues to characterize a widely accepted paradigm that ageing is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses. Inflammaging differs significantly from the traditional five cardinal features of acute inflammation in that it is characterized by a relative decline in adaptive immunity and T-helper 2 responses and is associated with increased innate immunity by cells of the mononuclear phagocyte lineage. While the over-active innate immunity characteristic of inflammaging may remain subclinical in many elderly individuals, a portion of individuals (postulated to have a "high responder inflammatory genotype") may shift from a state of "normal" or "subclinical" inflammaging to one or more of a number of age-associated diseases. We and others have found that IFN-gamma and other pro-inflammatory cytokines interact with processing and production of Abeta peptide, the pathological hallmark feature of Alzheimer's disease (AD), suggesting that inflammaging may be a "prodrome" to AD. Although conditions of enhanced innate immune response with overproduction of pro-inflammatory proteins are associated with both healthy aging and AD, it is suggested that those who age "well" demonstrate anti-inflammaging mechanisms and biomarkers that likely counteract the adverse immune response of inflammaging. Thus, opposing the features of inflammaging may prevent or treat the symptoms of AD. In this review, we fully characterize the aging immune system. In addition, we explain how three novel treatments, (1) human umbilical cord blood cells (HUCBC), (2) flavanoids, and (3) Abeta vaccination oppose the forces of inflammaging and AD-like pathology in various mouse models.

Townsend KP, Obregon D, Quadros A, Patel N, Volmar Ch, Paris D, Mullan M. · Department of Psychiatry, Roskamp Institute, University of South Florida, 3515 Fletcher Avenue, Tampa, FL 33613, USA. · Ann N Y Acad Sci. · Pubmed #12480734 No free full text.

Abstract: Abeta peptides are thought to be critical molecules in the pathophysiology of Alzheimer's disease (AD) and are the major protein constituents of senile plaques. In most AD cases, Abeta peptides also form some deposits in the cerebrovasculature, leading to cerebral amyloid angiopathy and hemorrhagic stroke. Regional cerebral hypoperfusion is one of the earlier clinical manifestations in both the sporadic and familial forms of AD. In addition, a variety of vascular risk factors of different etiologies (for instance, diabetes, hypertension, high cholesterol level, atherosclerosis, and smoking) constitute risk factors for AD as well, suggesting that functional vascular abnormalities may contribute to AD pathology. We studied the effect of Abeta on constrictor responses elicited by endothelin-1 in isolated human cerebral arteries collected following rapid autopsies. We report that freshly solubilized Abeta potentiates endothelin-1-induced vasoconstriction in isolated human middle cerebral and basilar arteries. The vasoconstriction elicited by Abeta in these large human cerebral arteries appears to be completely antagonized by NS-398, a selective cyclooxygenase-2 inhibitor, or by SB202190, a specific p38 mitogen-activated protein kinase inhibitor, suggesting that Abeta vasoactivity is mediated via the stimulation of a proinflammatory pathway. In addition, a similar proinflammatory response appears to be mediated by Abeta in isolated human brain microvessels, resulting in an increased production of prostaglandin E(2) and F(2alpha). Using a scanner laser Doppler imager, we show a progressive decline with aging in cortical perfusion level in transgenic APPsw mice (line 2576) compared with age-matched control littermates. The relation between the acute proinflammatory and vasoactive properties of Abeta and the chronic progressive hypoperfusion seen in AD (and transgenic models thereof) is yet to be elucidated.

Obregon D, Hou H, Bai Y, Nikolic WV, Mori T, Luo D, Zeng J, Ehrhart J, Fernandez F, Morgan D, Giunta B, Town T, Tan J. · Neuroimmunology Laboratory, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, USA. · Neurobiol Dis. · Pubmed #18055209 No free full text.

Abstract: Amyloid-beta (Abeta) immunization efficiently reduces amyloid plaque load and memory impairment in transgenic mouse models of Alzheimer's disease (AD). Active Abeta immunization has also yielded favorable results in a subset of AD patients. However, a small percentage of patients developed severe aseptic meningoencephalitis associated with brain inflammation and infiltration of T-cells. We have shown that blocking the CD40-CD40 ligand (L) interaction mitigates Abeta-induced inflammatory responses and enhances Abeta clearance. Here, we utilized genetic and pharmacologic approaches to test whether CD40-CD40L blockade could enhance the efficacy of Abeta(1-42) immunization, while limiting potentially damaging inflammatory responses. We show that genetic or pharmacologic interruption of the CD40-CD40L interaction enhanced Abeta(1-42) immunization efficacy to reduce cerebral amyloidosis in the PSAPP and Tg2576 mouse models of AD. Potentially deleterious pro-inflammatory immune responses, cerebral amyloid angiopathy (CAA) and cerebral microhemorrhage were reduced or absent in these combined approaches. Pharmacologic blockade of CD40L decreased T-cell neurotoxicity to Abeta-producing neurons. Further reduction of cerebral amyloidosis in Abeta-immunized PSAPP mice completely deficient for CD40 occurred in the absence of Abeta immunoglobulin G (IgG) antibodies or efflux of Abeta from brain to blood, but was rather correlated with anti-inflammatory cytokine profiles and reduced plasma soluble CD40L. These results suggest CD40-CD40L blockade promotes anti-inflammatory cellular immune responses, likely resulting in promotion of microglial phagocytic activity and Abeta clearance without generation of neurotoxic Abeta-reactive T-cells. Thus, combined approaches of Abeta immunotherapy and CD40-CD40L blockade may provide for a safer and more effective Abeta vaccine.

Nikolic WV, Bai Y, Obregon D, Hou H, Mori T, Zeng J, Ehrhart J, Shytle RD, Giunta B, Morgan D, Town T, Tan J. · Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa, FL 33613, USA. · Proc Natl Acad Sci U S A. · Pubmed #17264212 links to  free full text

Abstract: Alzheimer's disease (AD) immunotherapy accomplished by vaccination with beta-amyloid (Abeta) peptide has proved efficacious in AD mouse models. However, "active" Abeta vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) Abeta vaccination approach and evaluated efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage, in WT mice and a transgenic mouse model of AD. We demonstrate that t.c. immunization of WT mice with aggregated Abeta(1-42) plus the adjuvant cholera toxin (CT) results in high-titer Abeta antibodies (mainly of the Ig G1 class) and Abeta(1-42)-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the Abeta(1-42) immunogen, suggesting that these unique innate immune cells participate in Abeta(1-42) antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated Abeta(1-42) peptide plus CT. Similar to WT mice, PSAPP mice showed high Abeta antibody titers. Most importantly, t.c. immunization with Abeta(1-42) plus CT resulted in significant decreases in cerebral Abeta(1-40,42) levels coincident with increased circulating levels of Abeta(1-40,42), suggesting brain-to-blood efflux of Abeta. Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD.

Tan J, Town T, Crawford F, Mori T, DelleDonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ. · The Roskamp Institute, Department of Psychiatry, University of South Florida, 3515 East Fletcher Avenue, Tampa, Florida 33613, USA. · Nat Neurosci. · Pubmed #12402041 No free full text.

Abstract: We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid-beta peptide (Abeta), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing Abeta, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished Abeta levels and beta-amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of Abeta/beta-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of Abeta. Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40-CD40L interaction resulted in amyloidogenic APP processing. These findings suggest several possible mechanisms underlying mitigation of AD pathology in response to CD40L depletion, and validate the CD40-CD40L interaction as a target for therapeutic intervention in AD.

Town T, Tan J, Sansone N, Obregon D, Klein T, Mullan M. · The Roskamp Institute, University of South Florida, 3515 E. Fletcher Avenue, Tampa, FL 33613, USA. · Neurosci Lett. · Pubmed #11427310 No free full text.

Abstract: It has been demonstrated that immunization of transgenic mouse models of Alzheimer's disease (AD) with amyloid-beta1-42 peptide (Abeta1-42) results in amelioration of AD-like pathology, including reduced soluble and deposited beta-amyloid and decreased cognitive impairment. Based on the proposed importance of immunoglobulin G (IgG) anti-Abeta antibodies (Abs) in these effects, we sought to characterize these Abs in splenocytes from mice immunized with Abeta1-42. Data show that a more aggregated preparation of Abeta1-42 gives a robust IgG anti-Abeta Ab response, while these Abs are almost undetectable when a less aggregated preparation of Abeta1-42 is used as the immunogen. Importantly, IgG anti-Abeta Ab production is detected after just 12 weeks of Abeta1-42 treatment. Analysis of anti-Abeta Ab IgG isotypes reveals that the majority of these Abs are IgG1, with significantly fewer Abs of the IgG2a or IgG2b isotypes (IgG1>IgG2a>IgG2b), suggesting a T lymphocyte helper type II response after Abeta1-42 immunization. To determine the epitope of Abeta recognized by IgG anti-Abeta Abs, intact Abeta and Abeta peptide fragments were analyzed for their ability to bind these Abs. Data show that these Abs specifically recognize an amino-terminal epitope of Abeta between amino acids one and twelve, with higher affinity for a more soluble preparation of Abeta1-42. These data further indicate the immunogenic potential of Abeta1-42 and offer insight into the nature of the IgG anti-Abeta Ab response.