Transcutaneous ␤ -amyloid immunization reduces cerebral ␤ -amyloid deposits without T cell infiltration and microhemorrhage

Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa, FL 33613, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2007; 104(7):2507-12. DOI: 10.1073/pnas.0609377104
Source: PubMed


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.

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Available from: Jared Ehrhart, Oct 06, 2015
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    • "Several experimental immunizations, in animal models, are also utilizing the skin and nasal mucosa to deliver β amyloid. Nikolic et al. (2007) demonstrated that transcutaneous immunization with aggregated β amyloid peptide with adjuvant cholera toxin, lead to high titers of Aβ antibodies and lead to significant decreases in cerebral amyloid β levels. Other experiments show that Aβ derived peptides, with an adjuvant, delivered intranasally to mucosal epithelial tissues results in effective clearance of Aβ plaques and improvement of cognitive function in animal models of AD (Maier et al., 2005, 2006). "
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    ABSTRACT: Amyloidosis are a large group of conformational diseases characterized by abnormal protein folding and assembly which results in the accumulation of insoluble protein aggregates that may accumulate systemically or locally in certain organs or tissue. In local amyloidosis, amyloid deposits are restricted to a particular organ or tissue. Alzheimer's, Parkinson's disease, and amyotrophic lateral sclerosis are some examples of neurodegenerative amyloidosis. Local manifestation of protein aggregation in the skin has also been reported. Brain and skin are highly connected at a physiological and pathological level. Recently several studies demonstrated a strong connection between brain and skin in different amyloid diseases. In the present review, we discuss the relevance of the "brain-skin connection" in different neurodegenerative amyloidosis, not only at the pathological level, but also as a strategy for the treatment of these diseases.
    Frontiers in Neurology 01/2012; 3:5. DOI:10.3389/fneur.2012.00005
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    • "Nikolic et al. [101] APP/PSEN1dE9 "
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    ABSTRACT: There is substantial and compelling evidence that aggregation and accumulation of amyloid beta protein (Abeta) plays a pivotal role in the development of Alzheimer's disease (AD); thus, numerous strategies to prevent Abeta aggregation and accumulation or to facilitate removal of preexisting deposits of Abeta are being evaluated as ways to treat or prevent AD. Pre-clinical studies in mice demonstrate the therapeutic potential of altering Abeta deposition by inducing a humoral immune response to fibrillar Abeta42 (fAbeta42) or passively administering anti-Abeta antibodies (Abs), and both passive and active anti-Abeta immunotherapeutic approaches are now being tested in humans. Although a variety of mechanisms have been postulated regarding how Abeta immunotherapy might work to attenuate or in some circumstances clear Abeta from the brain, no mechanism has been definitively proven or disproven. Herein, we will review the various mechanisms that have been postulated. In addition we will discuss how a more thorough understanding of the pharmacokinetics of anti-Abeta Abs and their effects on Abeta levels and turnover provides insight into both the therapeutic potential and limitation of Abeta immunotherapy. We will conclude with a discussion of additional experimentation required to better understand the mechanism of action of anti-Abeta Abs in AD and optimize antibody (Ab) mediated therapy for AD.
    CNS & neurological disorders drug targets 04/2009; 8(1):31-49. · 2.63 Impact Factor
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    • "InteractionsbetweenHIVandmechanisms underlyingADmaycauseacceleratedand severedementias[8].Suchinteractionsmay occuratseverallevels.First,ithasbeenmost recentlydemonstratedthatthecysteine-rich domainofTatinteractswithneprilysin,atype IIplasmamembranezincmetallopeptidase whichcleavesthetoxicsecretedAβpeptide [10] [37] [82] [83].Second,Tatcandirectly inhibituptakeofAβandApo-E.Inthecaseof neurons,thisoccursthroughinhibitionofthe LRPreceptor[33].AsshowninFigures1and 2,Tatproteindose-dependentlydecreased uptakeofAβ1-42inmicrogliaaswell.We suggestextracellularenzymaticdegradationof thepeptidebyneprilysindoesnotaccountfor thisincreasedclearanceofAβas endopeptidaseactivityisgenerallynon- existentorminimalat4ºC[84].Indeed microgliaincubatedat4ºCinparallelcell cultureplatesunderthesametreatment conditionsdescribedabovedisplayedsimilar resultstothoseincubatedat37ºC.Infurther support,oursysteminvolvedwhole recombinantTatproteinwhereasDailyand colleaguesin2006reportedthatpeptides derivedfromtheTatprotein,butnotTat proteinitself,inhibitneprilysin[37]. Additionally,wesuggestcelldeathduetothe neurotoxicpropertiesofTat[24] [85] [86] [87]did notsignificantlyinfluencethephagocytic "
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    ABSTRACT: Human immunodeficiency virus (HIV)-associated dementia (HAD) is a subcortical neuropsychiatric syndrome that has increased in prevalence in the era of highly active antiretroviral therapy (HAART). Several studies demonstrated increased amyloidosis in brains of HIV patients and suggested that there may be a significant number of long-term HIV survivors with co-morbid Alzheimer's disease (AD) in the future. We show HIV-1 Tat protein inhibits microglial uptake of Abeta1-42 peptide, a process that is enhanced by interferon-gamma (IFN-gamma) and rescued by the STAT1 inhibitor (-)-epigallocatechin-3-gallate (EGCG). It is hypothesized that reduced Abeta uptake occurs through IFN-gamma mediated STAT1 activation. This process promotes a switch from a phagocytic to an antigen presenting phenotype in microglia through activation of class II transactivator (CIITA). Additionally, we show that HIV-1 Tat significantly disrupts apolipoprotein-3 (Apo-E3) promoted microglial Abeta uptake. As Tat has been shown to directly interact with the low density lipoprotein (LRP) receptor and thus inhibit the uptake of its ligands including apolipoprotein E4 (Apo-E4) and Abeta peptide in neurons, we further hypothesize that a similar inhibition of LRP may occur in microglia. Future studies will be required to fully characterize the mechanisms underlying IFN-gamma enhancement of HIV-1 Tats disruption of microglial phagocytosis of Abeta and Apo-E3.
    International journal of clinical and experimental pathology 02/2008; 1(3):260-75. · 1.89 Impact Factor
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