Biomedical subjects

Cynthia A Lemere

Publications and source records attributed to Cynthia A Lemere.

At least 19 recordsLinked to original sources

PubMed2006

Boosting with intranasal dendrimeric Abeta1-15 but not Abeta1-15 peptide leads to an effective immune response following a single injection of Abeta1-40/42 in APP-tg mice.

BACKGROUND: Immunotherapy for Alzheimer's disease (AD) is emerging as a potential treatment. However, a clinical trial (AN1792) was halted after adverse effects occurred in a small subset of subjects, which may have been caused by a T cell-mediated immunological response. In general, aging limits the humoral immune response, therefore, immunogens and vaccination regimes are required that induce a strong antibody response with less potential for an adverse immune response. METHOD: In the current study, we immunized both wildtype and J20 APP-tg mice with a priming injection of Abeta1-40/42, followed by multiple intranasal boosts with the novel immunogen dAbeta1-15 (16 copies of Abeta1-15 on a lysine tree), Abeta1-15 peptide or Abeta1-40/42 full length peptide. RESULTS: J20 APP-tg mice primed with Abeta1-40/42 subcutaneously and subsequently boosted intranasally with Abeta1-15 peptide did not generate a cellular or humoral immune response. In contrast, J20 APP-tg mice boosted intranasally with dAbeta1-15 or full length Abeta1-40/42 produced high levels of anti-Abeta antibodies. Splenocyte proliferation was minimal in mice immunized with dAbeta1-15. Wildtype littermates of the J20 APP-tg mice produced higher amounts of anti-Abeta antibodies compared to APP-tg mice but also had low T cell proliferation. The anti-Abeta antibodies were mainly composed of IgG2b and directed to an epitope within the Abeta1-7 region, regardless of the immunogen. Examination of the brain showed a significant reduction in Abeta plaque burden in the J20 APP-tg mice producing antibodies compared to controls. Biochemically, Abeta40 or Abeta42 were also reduced in brain homogenates and elevated in plasma but the changes did not reach significance. CONCLUSION: Our results demonstrate that priming with full length Abeta40/42 followed by boosting with dAbeta1-15 but not Abeta1-15 peptide led to a robust humoral immune response with a minimal T cell response in J20 APP-tg mice. In addition, Abeta plaque burden was reduced in mice producing anti-Abeta antibodies. Interestingly, wildtype mice produced higher levels of anti-Abeta antibodies, indicating that immune tolerance may be present in J20 APP-tg mice. Together, these data suggest that dAbeta1-15 but not Abeta1-15 peptide may be useful as a boosting immunogen in an AD vaccination regime.

Journal Article↗

PubMed2006

Dendrimeric Abeta1-15 is an effective immunogen in wildtype and APP-tg mice.

Immunization of humans and APP-tg mice with full-length beta-amyloid (Abeta) results in reduced cerebral Abeta levels. However, due to adverse events in the AN1792 trial, alternative vaccines are required. We investigated dendrimeric Abeta1-15 (dAbeta1-15), which is composed of 16 copies of Abeta1-15 peptide on a branched lysine core and thus, includes an Abeta-specific B cell epitope but lacks the reported T cell epitope. Immunization by subcutaneous, transcutaneous, and intranasal routes of B6D2F1 wildtype mice led to anti-Abeta antibody production. Antibody isotypes were mainly IgG1 for subcutaneous or transcutaneous immunization and IgG2b for intranasal immunization, suggestive of a Th2-biased response. All Abeta antibodies preferentially recognized an epitope in Abeta1-7. Intranasal immunization of J20 APP-tg mice resulted in a robust humoral immune response with a corresponding significant reduction in cerebral plaque burden. Splenocyte proliferation against Abeta peptide was minimal indicating the lack of an Abeta-specific cellular immune response. Anti-Abeta antibodies bound monomeric, oligomeric, and fibrillar Abeta. Our data suggest that dAbeta1-15 may be an effective and potentially safer immunogen for Alzheimer's disease (AD) vaccination.

Administration, Cutaneous↗

PubMed2006

Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer's disease mouse model in the absence of an Abeta-specific cellular immune response.

Amyloid-beta (Abeta) immunotherapy lowers cerebral Abeta and improves cognition in mouse models of Alzheimer's disease (AD). A clinical trial using active immunization with Abeta1-42 was suspended after approximately 6% of patients developed meningoencephalitis, possibly because of a T-cell reaction against Abeta. Nevertheless, beneficial effects were reported in antibody responders. Consequently, alternatives are required for a safer vaccine. The Abeta1-15 sequence contains the antibody epitope(s) but lacks the T-cell reactive sites of full-length Abeta1-42. Therefore, we tested four alternative peptide immunogens encompassing either a tandem repeat of two lysine-linked Abeta1-15 sequences (2xAbeta1-15) or the Abeta1-15 sequence synthesized to a cross-species active T1 T-helper-cell epitope (T1-Abeta1-15) and each with the addition of a three-amino-acid RGD (Arg-Gly-Asp) motif (R-2xAbeta1-15; T1-R-Abeta1-15). High anti-Abeta antibody titers were observed in wild-type mice after intranasal immunization with R-2xAbeta1-15 or 2xAbeta1-15 plus mutant Escherichia coli heat-labile enterotoxin LT(R192G) adjuvant. Moderate antibody levels were induced after immunization with T1-R-Abeta1-15 or T1-Abeta1-15 plus LT(R192G). Restimulation of splenocytes with the corresponding immunogens resulted in moderate proliferative responses, whereas proliferation was absent after restimulation with full-length Abeta or Abeta1-15. Immunization of human amyloid precursor protein, familial AD (hAPP(FAD)) mice with R-2xAbeta1-15 or 2xAbeta1-15 resulted in high anti-Abeta titers of noninflammatory T-helper 2 isotypes (IgG1 and IgG2b), a lack of splenocyte proliferation against full-length Abeta, significantly reduced Abeta plaque load, and lower cerebral Abeta levels. In addition, 2xAbeta1-15-immunized hAPP(FAD) animals showed improved acquisition of memory compared with vehicle controls in a reference-memory Morris water-maze behavior test that approximately correlated with anti-Abeta titers. Thus, our novel immunogens show promise for future AD vaccines.

Alzheimer Disease↗

PubMed2006

Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice.

Activated microglia and reactive astrocytes invade and surround cerebral beta amyloid (Abeta) plaques in Alzheimer's disease (AD), but the role of microglia in plaque development is still unclear. In this study, minocycline was administered for 3 months, prior to and early in Abeta plaque formation in amyloid precursor protein transgenic mice (APP-tg). When minocycline was given to younger mice, there was a small but significant increase in Abeta deposition in the hippocampus, concurrent with improved cognitive performance relative to vehicle treated mice. If APP-tg mice received minocycline after Abeta deposition had begun, microglial activation was suppressed but this did not affect Abeta deposition or improve cognitive performance. In vitro studies demonstrated that minocycline suppressed microglial production of IL-1beta, IL-6, TNF, and NGF. Thus, minocycline has different effects on Abeta plaque deposition and microglia activation depending on the age of administration. Our data suggest that this may be due to the effects of minocycline on microglial function. Therefore, anti-inflammatory therapies to suppress microglial activation or function may reduce cytokine production but enhance Abeta plaque formation early in AD.

Age Factors↗

PubMed2006

Effects of huperzine A on amyloid precursor protein processing and beta-amyloid generation in human embryonic kidney 293 APP Swedish mutant cells.

The amyloid precursor protein (APP) is cleaved enzymatically by nonamyloidogenic and amyloidogenic pathways. alpha-Secretase (alpha-secretase), cleaves APP within the beta-amyloid (Abeta) sequence, resulting in the release of a secreted fragment of APP (alphaAPPs) and precluding Abeta generation. In this study, we investigated the effects of an acetylcholinesterase inhibitor, huperzine A (Hup A), on APP processing and Abeta generation in human embryonic kidney 293 cells transfected with human APP bearing the Swedish mutation (HEK293 APPsw). Hup A dose dependently (0-10 microM) increased alphaAPPs release and membrane-coupled APP CTF-C83, suggesting increased APP metabolism toward the nonamyloidogenic alpha-secretase pathway. The metalloprotease inhibitor TAPI-2 inhibited the Hup A-induced increase in alphaAPPs release, further suggesting a modulatory effect of Hup A on alpha-secretase activity. The synthesis of full-length APP and cell viability were unchanged after Hup A incubation, whereas the level of Abeta(Total) was significantly decreased, suggesting an inhibitory effect of Hup A on Abeta production. Hup A-induced alphaAPPs release was significantly reduced by the protein kinase C (PKC) inhibitors GF109203X and Calphostin C. These data, together with the finding that the PKCalpha level was enhanced prior to the increase of alphaAPPs secretion, indicate that PKC may be involved in Hup A-induced alphaAPPs secretion by HEK293 APPsw cells. Our data suggest alternative pharmacological mechanisms of Hup A relevant to the treatment of Alzheimer's disease.

Alkaloids↗

PubMed2006

Amyloid-beta immunotherapy for the prevention and treatment of Alzheimer disease: lessons from mice, monkeys, and humans.

Alzheimer disease (AD), the most common form of dementia, is without an effective cure or preventive treatment. Recently, amyloid-beta protein (Abeta) has become a major therapeutic target. Many efforts are underway to either reduce the production of Abeta or enhance its clearance. In 1999, Schenk and colleagues first showed that active immunization with full-length Abeta lowered cerebral Abeta levels in transgenic mice. These findings have been confirmed and extended in various transgenic mouse models of AD using both active and passive Abeta immunization. Cognitive improvement also has been reported in association with active and passive Abeta vaccination in AD-like mouse models, even in the absence of significant reductions in cerebral Abeta loads. In 2004, the authors reported that active immunization with full-length Abeta in aged nonhuman primates, Caribbean vervets, reduced cerebral Abeta levels and gliosis. Proposed mechanisms of Abeta clearance by immunotherapy include disruption of Abeta aggregates, Abeta phagocytosis by microglia, neutralization of Abeta oligomers at the synapse, and increased efflux of Abeta from brain to blood. A phase IIa clinical trial was halted in 2002 because of the appearance of meningoencephalitis in approximately 6% of the AD patients. Although the exact cause of these adverse events is unknown, the immunogen, full-length Abeta1-42, may have been recognized as a self-antigen leading to an autoimmune response in some patients. Limited cognitive stabilization and apparent plaque clearance have been reported in subsets of patients who generated antibody titers. Currently, a passive immunization trial with a recombinant humanized monoclonal Abeta antibody is underway in humans. In the meantime, the authors are developing novel Abeta peptide immunogens for active immunization to target Abeta B cell epitope(s) and avoid Abeta-specific T-cell reactions in order to generate a safe and effective AD vaccine. The authors remain optimistic about the potential of such a vaccine for the prevention and treatment of AD.

Alzheimer Disease↗

PubMed2005

Modulation of the humoral and cellular immune response in Abeta immunotherapy by the adjuvants monophosphoryl lipid A (MPL), cholera toxin B subunit (CTB) and E. coli enterotoxin LT(R192G).

Abeta vaccination or passive transfer of human-specific anti-Abeta antibodies are approaches under investigation to prevent and/or treat Alzheimer's disease (AD). Successful active Abeta vaccination requires a strong and safe adjuvant to induce anti-Abeta antibody formation. We compared the adjuvants monophosphoryl lipid A (MPL)/trehalose dicorynomycolate (TDM), cholera toxin B subunit (CTB) and Escherichia coli heat-labile enterotoxin LT(R192G) for their ability to induce a humoral and cellular immune reaction, using fibrillar Abeta1-40/42 as a common immunogen in wildtype B6D2F1 mice. Subcutaneous (s.c.) administration with MPL/TDM resulted in anti-Abeta antibodies levels up to four times higher compared to s.c. LT(R192G). Using MPL/TDM, the anti-Abeta antibodies induced were mainly IgG2b, IgG1 and lower levels of IgG2a and IgM, with a moderate splenocyte proliferation and IFN-gamma production in vitro upon stimulation with Abeta1-40/42. LT(R192G), previously shown by us to induce robust titers of anti-Abeta antibodies, generated predominantly IgG2b and IgG1 anti-Abeta antibodies with very low splenocyte proliferation and IFN-gamma production. Weekly intranasal (i.n.) administration over 11 weeks of Abeta40/42 with CTB induced only moderate levels of antibodies. All immunogens generated antibodies that recognized mainly the Abeta1-7 epitope and specifically detected amyloid plaques on AD brain sections. In conclusion, MPL/TDM, in addition to LT(R192G), is an effective adjuvant when combined with Abeta40/42 and may aid in the design of Abeta immunotherapy.

Adjuvants, Immunologic↗

PubMed2005

Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo.

One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (Abeta), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Abeta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Abeta species in the brain. Intracerebroventricular injection of naturally secreted human Abeta inhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Abeta completely prevented the inhibition of LTP when injected after Abeta. Size fractionation showed that Abeta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Abeta antibody again prevented such inhibition. Active immunization against Abeta was partially effective, and the effects correlated positively with levels of antibodies to Abeta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Abeta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.

Alzheimer Disease↗

PubMed2005

Developing novel immunogens for an effective, safe Alzheimer's disease vaccine.

Active amyloid beta (A beta) vaccination has been shown to be effective in clearing cerebral A beta and improving cognitive function in mouse models of Alzheimer's disease. However, an A beta vaccine clinical trial was suspended after meningoencephalitis was detected in a subset of subjects. Passive immunization has been suggested to be a safer alternative to active A beta immunization but there are reports of increased risk of microhemorrhages associated with its administration in aged beta-amyloid precursor protein transgenic mice bearing abundant vascular amyloid deposition. In addition, the cost may be prohibitive for large-scale clinical use. Therefore, we are designing novel A beta immunogens that encompass the B cell epitope of A beta but lack the T cell-reactive sites. These immunogens induced the production of A beta-specific antibodies in the absence of an A beta-specific cellular immune response in wild-type mice and are being tested in beta-amyloid precursor protein transgenic mice. These data together with published reports from several other groups suggest that a safe, active A beta vaccine is a tenable goal.

Alzheimer Disease↗

PubMed2004

Differences in the immune response to long term Abeta vaccination in C57BL/6 and B6D2F1 mice.

The cerebral accumulation of beta-amyloid (Abeta) is a pathological hallmark of Alzheimer's disease (AD). Abeta vaccination or anti-Abeta specific antibodies may be a possible therapeutic option for AD. Previously, we demonstrated variation in the humoral response between B6D2F1 and C57BL/6 during short term (14 weeks) Abeta immunization. In the present study, we determined the humoral and cellular immune responses in these same mouse strains to a longer period of Abeta vaccination and further refined the major B cell epitope to Ass1-7. B6D2F1 mice generated a greater humoral and Th1 immune response versus C57BL/6 mice. Immunization with 25 microg Abeta produced a greater T cell response in B6D2F1 mice compared to 50 or 100 microg Abeta but resulted in comparable humoral immunity. Thus, Abeta vaccination is affected by the genetic background and amount of Abeta peptide used as immunogen. These data may help explain some differences observed in Abeta immunization studies in mice of various genetic backgrounds and aid in the design of Abeta vaccines.

Alzheimer Vaccines↗

PubMed2004

Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice.

Mutations in presenilins (PS) 1 and 2 are the major cause of familial Alzheimer's disease. Conditional double knock-out mice lacking both presenilins in the postnatal forebrain (PS cDKO mice) exhibit memory and synaptic plasticity impairments followed by progressive neurodegeneration in the cerebral cortex. Here we further investigate the molecular events that may underlie the observed phenotypes and identify additional neuropathological markers in the PS cDKO brain. Enzyme-linked immunosorbent assay analysis showed reduced levels of the toxic beta-amyloid (Abeta) peptides in the cerebral cortex of PS cDKO mice. Interestingly, the reduction in Abeta40 and Abeta42 peptides is similar in PS1 conditional knock-out and PS cDKO mice. We further examined the gene expression profile by oligonucleotide microarrays in the PS cDKO cerebral cortex and found that a high number of genes are differentially expressed, most notably a group of up-regulated inflammatory genes. Quantitative real-time reverse transcription PCR and Western analyses confirmed the elevated levels of glial fibrillary acidic protein, complement component C1q, and cathepsin S, up-regulation of which has been associated with inflammatory responses in various neurodegenerative processes. Immunohistochemical analysis revealed that the increase in complement component C1q is confined to the hippocampal formation, whereas glial fibrillary acidic protein and cathepsin S are up-regulated throughout the entire neocortex and hippocampus. In addition, strong microglial activation occurs in the hippocampus and the deeper cortical layers of PS cDKO mice. These results indicate that the memory impairment and neurodegeneration in PS cDKO mice are not caused by Abeta accumulation and that loss of PS function leads to differential up-regulation of inflammatory markers in the cerebral cortex.

Amyloid beta-Peptides↗

PubMed2004

A seed for Alzheimer amyloid in the brain.

A fundamental question about the early pathogenesis of Alzheimer's disease (AD) concerns how toxic aggregates of amyloid beta protein (Abeta) are formed from its nontoxic soluble form. We hypothesized previously that GM1 ganglioside-bound Abeta (GAbeta) is involved in the process. We now examined this possibility using a novel monoclonal antibody raised against GAbeta purified from an AD brain. Here, we report that GAbeta has a conformation distinct from that of soluble Abeta and initiates Abeta aggregation by acting as a seed. Furthermore, GAbeta generation in the brain was validated by both immunohistochemical and immunoprecipitation studies. These results imply a mechanism underlying the onset of AD and suggest that an endogenous seed can be a target of therapeutic strategy.

Adult↗

PubMed2004

Alzheimer's Abeta vaccination of rhesus monkeys (Macaca mulatta).

Recent preliminary data suggest that vaccination with Alzheimer's Abeta might reduce senile plaque load and stabilize cognitive decline in human Alzheimer's disease. To examine the mechanisms and consequences of anti-Abeta-antibody formation in a species more closely related to humans, rhesus monkeys (Macaca mulatta) were vaccinated with aggregated Abeta(1-42). Immunized monkeys developed anti-Abeta titers exceeding 1:1000, and their plasma Abeta levels were 5-10-fold higher than the plasma Abeta levels observed in monkeys vaccinated with aggregated amylin. These data support the use of non-human primates to model certain phenomena associated with vaccination of humans with aggregated Alzheimer's Abeta.

Aging↗

PubMed2004

Species-specific immune response to immunization with human versus rodent A beta peptide.

Amyloid beta (A beta) immunization of amyloid precursor protein (APP)-transgenic (tg) mice with human A beta induces humoral immunity, however, the immune response to endogenous rodent A beta is unknown. Fourteen-month J20 APP-tg mice and non-tg littermates were immunized subcutaneously followed by chronic intranasal boosting with human or rodent A beta peptide and adjuvant LT(R192G). Rodent A beta-immunized APP-tg mice had anti-rodent A beta antibody levels of 257.8 micrograms/ml and those immunized with human A beta had anti-human A beta antibodies of 120.8 micrograms/ml. Non-tg littermates had anti-rodent and anti-human A beta antibody concentrations of 98.8 and 231.1 microgram/ml, respectively. Inter-species cross-reactivity was minimal. Anti-human A beta antibodies were predominately IgG1 and IgG2b, while anti-rodent A beta antibodies were equally IgG1, IgG2a, and IgG2b. Anti-human A beta antibodies recognized an epitope within human A beta1-9. Anti-rodent A beta antibodies did not stain Alzheimer's disease (AD) plaques but bound some plaques in APP-tg mice. Splenocytes proliferated modestly to their respective antigen and secreted low levels of IL-2 and IFN-gamma. Therefore, immunizing APP-tg and non-tg mice with rodent A beta resulted in a species-specific humoral response with modest T cell reactivity.

Alzheimer Disease↗

PubMed2004

Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet.

Amyloid beta (Abeta) protein immunotherapy lowers cerebral Abeta and improves cognition in mouse models of Alzheimer's disease (AD). Here we show that Caribbean vervet monkeys (Chlorocebus aethiops, SK) develop cerebral Abeta plaques with aging and that these deposits are associated with gliosis and neuritic dystrophy. Five aged vervets were immunized with Abeta peptide over 10 months. Plasma and cerebral spinal fluid (CSF) samples were collected periodically from the immunized vervets and five aged controls; one monkey per group expired during the study. By Day 42, immunized animals generated plasma Abeta antibodies that labeled Abeta plaques in human, AD transgenic mouse and vervet brains; bound Abeta1-7; and recognized monomeric and oligomeric Abeta but not full-length amyloid precursor protein nor its C-terminal fragments. Low anti-Abeta titers were detected in CSF. Abetax-40 levels were elevated approximately 2- to 5-fold in plasma and decreased up to 64% in CSF in immunized vervets. Insoluble Abetax-42 was decreased by 66% in brain homogenates of the four immunized animals compared to archival tissues from 13 age-matched control vervets. Abeta42-immunoreactive plaques were detected in frontal cortex in 11 of the 13 control animals, but not in six brain regions examined in each of the four immunized vervets. No T cell response or inflammation was observed. Our study is the first to demonstrate age-related Abeta deposition in the vervet monkey as well as the lowering of cerebral Abeta by Abeta vaccination in a non-human primate. The findings further support Abeta immunotherapy as a potential prevention and treatment of AD.

Age Factors↗

PubMed2003

APP processing is regulated by cytoplasmic phosphorylation.

Amyloid-beta peptide (Abeta) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the beta-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by alpha-secretase. The production of Abeta is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Abeta generation.

Alzheimer Disease↗

PubMed2003

Abeta1-15 is less immunogenic than Abeta1-40/42 for intranasal immunization of wild-type mice but may be effective for "boosting".

Immunizing mouse models of Alzheimer's disease (AD) against beta-amyloid (Abeta) leads to a decrease in cerebral Abeta burden as well as an improvement in behavioral deficits. Circulating Abeta-antibodies may be responsible for interfering with Abeta deposition. In the present study, we attempted to initiate more robust antibody production in wild type (WT) mice. Three immunization strategies were examined: intranasal (i.n.) immunization with Abetal-15 or full-length Abeta1-40/42, i.n. administration of Abeta combined with mucosal adjuvants, native labile enterotoxin (LT) or its non-toxic form, LT(R192G), and prime-boost regimes. Using Abeta1-15 as the primary immunogen for intranasal immunization did not initiate strong antibody production. When Abeta1-15 or Abeta1-40/42 was combined with native LT or LT(R192G), antibody production was significantly increased. Nasal immunization with Abeta1-15 and native LT successfully "boosted" an immune response "primed" by an intraperitoneal (i.p.) injection of Abeta1-40/42, producing moderately high Abeta titers that remained stable for at least 6 months. Serum anti-Abeta antibodies, regardless of the length of the Abeta immunogen, consistently detected human AD plaques, had epitopes within Abeta1-15, and were predominantly of the IgG2b, IgG1, and IgG2a isotypes. The adjuvants were well-tolerated in the mice. Thus, Abeta1-15 may have potential as a safer, more cost-effective "boosting" immunogen than the full-length Abeta peptide for chronic, active Abeta immunization.

Administration, Intranasal↗

PubMed2003

Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP mice.

Immunization with amyloid-beta (Abeta) peptide in mouse models of Alzheimer's disease has been reported to decrease cerebral Abeta levels and improve behavioral deficits. Several mechanisms have been proposed, including antibody-induced phagocytosis of Abeta by cerebral microglia and increased efflux of Abeta from the brain to the periphery. The latter mechanism was suggested in mice undergoing acute, passive transfer of an Abeta monoclonal antibody. Here, PSAPP transgenic mice were actively immunized by a single intraperitoneal injection of synthetic Abeta followed by chronic intranasal administration of Abeta with the mucosal adjuvant, Escherichia coli heat-labile enterotoxin, LT, twice weekly for 8 weeks. Serum from Abeta-immunized mice had an average of 240 microg/ml of anti-Abeta-specific antibodies; these antibodies had epitope(s) within Abeta1-15 and were of immunoglobulin (Ig) isotypes IgG2b, IgG2a, and IgG1. Immunization led to a 75% decrease in plaque number (P < 0.0001) and a 58% decrease in Abetax-42 levels (P < 0.026) in brain, and gliosis and neuritic dystrophy were diminished. No pathological effects of the immunization were observed in kidney, spleen, or snout. Serum Abeta levels increased 28-fold in immunized mice (53.06 ng/ml) compared to controls (1.87 ng/ml). Most of the Abeta in the serum of the immunized mice was bound to antibodies. We conclude that following active immunization, anti-Abeta antibodies sequester serum Abeta and may increase central nervous system to serum Abeta clearance.

Amyloid beta-Peptides↗