Novel Therapeutic Approach for the Treatment of Alzheimer's Disease by Peripheral Administration of Agents with an Affinity to β-Amyloid

Matsuoka, Yasuji; Shimada, Mitsuo; LaFrancois, John; Saito, Mariko; Gaynor, Kate; Olm, Vicki; Wang, Lili; Casey, Evelyn; Lu, Yifan; Shiratori, Chiharu; Lemere, Cynthia A.; Duff, Karen

doi:10.1523/jneurosci.23-01-00029.2003

Cited by 316 publications

(217 citation statements)

References 26 publications

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“…However, in several reports, behavioral improvements occurred acutely, before any change in plaque density, suggesting the Ab association with particular soluble A␤ species is responsible for improved function. Two non-Ig proteins, RAGE and gelsolin, have been shown to bind A␤ and, when administered peripherally, to decrease brain A␤ load (Deane et al, 2003;Matsuoka et al, 2003;Arancio et al, 2004). This supports the peripheral sink hypothesis for passive immunization against A␤.…”

Section: Introductionsupporting

confidence: 58%

Subcutaneous Nogo Receptor Removes Brain Amyloid-β and Improves Spatial Memory in Alzheimer's Transgenic Mice

Park

Widi²,

Gimbel³

et al. 2006

J. Neurosci.

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The production and aggregation of cerebral amyloid-␤ (A␤) peptide are thought to play a causal role in Alzheimer's disease (AD). Previously, we found that the Nogo-66 receptor (NgR) interacts physically with both A␤ and the amyloid precursor protein (APP). The inverse correlation of A␤ levels with NgR levels within the brain may reflect regulation of A␤ production and/or A␤ clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated A␤ clearance in APPswe/PSEN-1⌬E9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15-28 aa of A␤ associate with specific surface-accessible patches on the leucine-rich repeat concave side of the solenoid structure of NgR. In transgenic mice, subcutaneous NgR(310)ecto-Fc treatment reduces brain A␤ plaque load while increasing the relative levels of serum A␤. These changes in A␤ are correlated with improved spatial memory in the radial arm water maze. The benefits of peripheral NgR administration are evident when therapy is initiated after disease onset. Thus, the peripheral association of NgR(310)ecto-Fc with central A␤ residues provides an effective therapeutic approach for AD.

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Section: Introductionsupporting

confidence: 58%

Subcutaneous Nogo Receptor Removes Brain Amyloid-β and Improves Spatial Memory in Alzheimer's Transgenic Mice

Park

Widi²,

Gimbel³

et al. 2006

J. Neurosci.

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“…In support of peripheral sink hypothesis (21,22) we quantified A␤ levels in the blood by ELISA and found significantly increased circulating A␤ 42 in PSAPP mice t.c.-immunized with A␤/CT as early as 4 weeks after immunization ( Fig. 2 B and C).…”

Section: Tc Immunization Of Psapp Mice With A␤ Plus Ct Results In Asupporting

confidence: 59%

“…6). These data suggest that circulating A␤ antibodies play an important role in clearance of A␤ from brain to blood via the peripheral sink hypothesis (21,22). This effect is likely not solely responsible for reduced cerebral amyloidosis, as, interestingly, we detected A␤ antibodies in brain homogenates from A␤/CT t.c.-immunized PSAPP mice [18.87 Ϯ 6.25 (mean ng/mg of total protein Ϯ SD)], whereas A␤ antibodies were undetectable in PSAPP mice t.c.-immunized with CT alone (data not shown).…”

Section: Psapp Mice Tc-immunized With A␤ Plus Ct Show Reduced Cerebralmentioning

confidence: 85%

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

Nikolic¹,

Bai²,

Obregon³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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This therapeutic approach is clearly highly efficacious; however, the safety of this strategy has become an important concern. In a recent clinical trial, patients were administered a synthetic A␤ peptide (AN-1792) plus adjuvant, and Ϸ6% of these patients developed aseptic meningoencephalitis, most likely mediated by braininfiltrating activated T cells (3,4). This serious side effect led to suspension of the clinical trial. Furthermore, passive transfer of A␤ antibodies to transgenic AD mice results in cerebral microhemorrhage, a potentially adverse side effect (5, 6). Uncovering of these adverse events has redirected A␤ vaccination strategies toward the goal of developing an approach that is both safe and effective.Studies examining the brains of A␤-vaccinated patients developing meningoencephalitis implicate A␤-reactive T cell subsets as major components of this deleterious response to active A␤ vaccination (7, 8). To subvert possible meningoencephalitis resulting from A␤ vaccination, various strategies have been attempted. Interestingly, recent works suggest that A␤-derived peptides delivered intranasally (with adjuvant) to mucosal epithelial tissues results in effective clearance of A␤ plaques and improvement of cognitive function in animal models of AD. Moreover, T cell reactivity appeared to be considerably reduced compared with other active immunization strategies. In other studies, differential T cell responses depended on the epitope/fragment of A␤ peptide used for vaccination. Specifically, portions of the A␤ peptide seemed to stimulate different T cell responses, resulting in either proinflammatory T helper (Th) cell type 1 (Th1) responses or antiinflammatory Th cell type 2 (Th2) responses (9, 10). Such findings imply that A␤ vaccination is not only efficacious, but may also prove to be safe and therefore a feasible strategy for AD therapy depending on a number of factors, including route of delivery, adjuvant choice, and A␤ epitope administered.The skin is a well established effective route for vaccination, including delivery of peptide-based vaccines (11-13). Strong humoral and cellular immune responses have been elicited after transcutaneous (t.c.) vaccination (14), largely owing to the diverse populations of resident antigen-presenting cells (APCs) and other immune cells in the various dermal layers. Subsets of dermalresident Langerhans cell (LC) precursors, known as migratory CD14 ϩ LC precursors, are important immune regulators that demonstrate ''professional'' APC capability, including reducing T cell stimulatory function by producing antiinflammatory cytokines (15). Also, skin-resident keratinocytes release the antiinflammatory cytokine IL-10 in response to certain stimuli. Keratinocytederived IL-10 serves to buffer harmful proinflammatory immune activation and thereby preserves skin barrier integrity (16).Taken together, these lines of evidence led us to hypothesize that targeting A␤ immunotherapy to skin tissue might provide an immunotherapeutic approach that is both efficacious and safe. In...

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“…Matusoka et al 177 investigated a different approach to enhance transport of Ab across the BBB into the periphery. In young transgenic mice, treatment with gelsolin or GM1 (a ganglioside), both agents with high affinity for Ab, resulted in a reduction in CNS Ab1-40 and Ab1-42 levels and a reduction in Ab plaque load.…”

Section: Ab Clearance Mechanismsmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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Novel Therapeutic Approach for the Treatment of Alzheimer's Disease by Peripheral Administration of Agents with an Affinity to β-Amyloid

Cited by 316 publications

References 26 publications

Subcutaneous Nogo Receptor Removes Brain Amyloid-β and Improves Spatial Memory in Alzheimer's Transgenic Mice

Subcutaneous Nogo Receptor Removes Brain Amyloid-β and Improves Spatial Memory in Alzheimer's Transgenic Mice

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

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

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