Toward modeling hemorrhagic and encephalitic complications of Alzheimer amyloid-β vaccination in nonhuman primates

Gandy, Sam; Walker, Lary C.

doi:10.1016/j.coi.2004.08.002

Cited by 25 publications

(15 citation statements)

References 55 publications

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“…A major question that arises regarding the antibodyindependent strategy we have described is whether the induction of an inflammatory response in the brains of humans that includes a Th1 component will have untoward side effects (50)(51)(52). It is postulated that the meningoencephalitis observed following Aβ immunization was related to the induction of Aβ-reactive T cells, and we have shown that there is increased T cell reactivity to Aβ in elderly individuals (53).…”

Section: Figurementioning

confidence: 99%

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Frenkel¹,

Maron²,

Burt³

et al. 2005

J. Clin. Invest.

163

115

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Amyloid β-peptide (Aβ) appears to play a key pathogenic role in Alzheimer disease (AD). Immune therapy in mouse models of AD via Aβ immunization or passive administration of Aβ antibodies markedly reduces Aβ levels and reverses behavioral impairment. However, a human trial of Aβ immunization led to meningoencephalitis in some patients and was discontinued. Here we show that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans plus glatiramer acetate, an FDA-approved synthetic copolymer used to treat multiple sclerosis, potently decreases Aβ plaques in an AD mouse model. This effect did not require the presence of antibody, as it was observed in B cell-deficient (Ig m-null) mice. Vaccinated animals developed activated microglia that colocalized with Aβ fibrils, and the extent of microglial activation correlated strongly with the decrease in Aβ fibrils. Activation of microglia and clearing of Aβ occurred with the adjuvant alone, although to a lesser degree. Our results identify a novel approach to immune therapy for AD that involves clearing of Aβ through the utilization of compounds that have been safely tested on or are currently in use in humans. IntroductionAlzheimer disease (AD) is the most common form of senile dementia, affecting more than 18 million people worldwide. With increased life expectancy, this number is expected to rise in the future. AD is characterized by widespread functional disturbance of the human brain. The classical neuropathological features are senile plaques, neurofibrillary tangles composed of paired helical filaments, and dystrophic neuritis. Compact senile plaques composed of amyloid β-peptide (Aβ) fibrils are associated with pathological changes in the surrounding brain neurons that lead to their death. Aβ appears to play a key pathogenic role in AD (1), and studies have connected the Aβ plaque with formation of intracellular tau tangles, another neurotoxic feature of AD (2, 3).A body of work has accumulated demonstrating that anti-Aβ antibodies are effective in clearance of amyloid deposits in vitro and in amyloid precursor protein-Tg (APP-Tg) mice (4-10). Solomon et al. showed in vitro that anti-Aβ antibodies can lead to disaggregation of Aβ fibrils, restoring Aβ solubility and thus prevent neurotoxic effects on cell lines (11, 12). Schenk et al. then demonstrated that parenteral immunization of APP-Tg mice with synthetic Aβ in complete Freund adjuvant (CFA) markedly decreased the number and density of Aβ deposits in the brain, with concomitant

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Section: Figurementioning

confidence: 99%

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Frenkel¹,

Maron²,

Burt³

et al. 2005

J. Clin. Invest.

163

115

View full text Add to dashboard Cite

show abstract

“…Although these incidents manifested themselves only in a minority of patients (<6%), a suspension of the multicenter study was deemed appropriate, and no further patients have been vaccinated in the past two years. The underlying pathophysiological mechanisms of these effects are elegantly reviewed by Gandy and Walker [17], who demonstrate the eminent usefulness of a primate model of this disease. One -still unproven -assumption predicts that the beneficial effects of anti-Ab vaccination are primarily brought about by immunoglobulins, whereas the detrimental effects may be mediated by cytotoxic T lymphocytes.…”

Section: Abbreviations Admentioning

confidence: 99%

The immune component of brain disease

Aguzzi

2004

Current Opinion in Immunology

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“…[6, 56, 57, 59, 62, 74]The precise mechanism whereby this occurs is unknown. Data from studies investigating passive immunotherapy in a variety of non-AD conditions suggest that the occurrence of vasogenic edema is non-specific, may not be directly related to specific immune targeting of Aβ, and may be important for safety monitoring of any passive immunization strategy in AD irrespective of the antibody used.…”

Section: 0 Expert Opinionmentioning

confidence: 99%

Is passive immunization for Alzheimer's disease ‘alive and well’ or ‘dead and buried’?

Jicha

2009

Expert Opinion on Biological Therapy

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Passive immunization strategies are under widespread investigation as potential disease-modifying therapies for AD. The development of and interest in passive immunization strategies for AD stemmed from a search for safer methods of delivering immunotherapy following the initial results of active vaccination with AN-1792, which led to the development of meningoencephalitis in 6% of vaccinated subjects in this trial. Current approaches based on promising data demonstrating behavioral improvement and reduced pathology in transgenic animal models of AD have focused exclusively on the immune targeting of β-amyloid. Preliminary results from three phase II trials of passive immunization were recently reported at the 2008 International Conference on Alzheimer's Disease suggest both promise and the need to exercise caution with this "safer" method of immunotherapy for AD. The antibody strategies used in each of these trials were distinct, using monoclonal N-terminal, central epitope, and polyclonal strategies in an effort to maximize the efficacy and safety of each approach. The tested compounds are all moving into phase III human trials of mild to moderate AD currently. We anxiously await the exciting discoveries that may come from the currently active phase III studies that may help yield the first disease modifying therapy for AD.

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Toward modeling hemorrhagic and encephalitic complications of Alzheimer amyloid-β vaccination in nonhuman primates

Cited by 25 publications

References 55 publications

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

The immune component of brain disease

Is passive immunization for Alzheimer's disease ‘alive and well’ or ‘dead and buried’?

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