β-Amyloid Immunotherapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease

Buttini, Manuel; Masliah, Eliezer; Barbour, Robin; Grajeda, Henry; Motter, Ruth; Johnson-Wood, Kelly; Khan, Karen; Seubert, Peter; Freedman, Stephen B.; Schenk, Dale; Games, Dora

doi:10.1523/jneurosci.1697-05.2005

Cited by 170 publications

(138 citation statements)

References 43 publications

(69 reference statements)

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“…However, most likely A␤ is the offending molecule. Given that synaptophysin deficits correlate with A␤ and not APP levels in multiple transgenic mouse lines (23) and can be specifically modified by passive immunization with anti-A␤ antibodies that have no effect on APP (50), the parsimonious conclusion is that A␤ itself is causing synaptic deficits in the PDAPP model.…”

Section: Discussionmentioning

confidence: 99%

“…Indirect evidence supports the notion that soluble A␤ assemblies and not A␤ plaques are responsible for synaptic toxicity in APP transgenic mice (23, 49 -52). SYN deficits correlate with levels of soluble A␤ but do not correlate with plaque load on an animal by animal basis (23,50). Therefore, quantitation of SYN provides a measure of plaque-independent AD-like pathology in the brains of PDAPP mice.…”

Section: Heterozygous Bace1 Gene Knock-out Has a Modest Effect On Solmentioning

confidence: 99%

See 1 more Smart Citation

Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice

McConlogue

Buttini

Anderson

et al. 2007

Journal of Biological Chemistry

277

226

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The aspartyl protease ␤-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates processing of amyloid precursor protein (APP) into amyloid ␤ (A␤) peptide, the major component of Alzheimer disease (AD) plaques. To determine the role that BACE1 plays in the development of A␤-driven AD-like pathology, we have crossed PDAPP mice, a transgenic mouse model of AD overexpressing human mutated APP, onto mice with either a homozygous or heterozygous BACE1 gene knockout. Analysis of PDAPP/BACE(؊/؊) mice demonstrated that BACE1 is absolutely required for both A␤ generation and the development of age-associated plaque pathology. Furthermore, synaptic deficits, a neurodegenerative pathology characteristic of AD, were also reversed in the bigenic mice. To determine the extent of BACE1 reduction required to significantly inhibit pathology, PDAPP mice having a heterozygous BACE1 gene knock-out were evaluated for A␤ generation and for the development of pathology. Although the 50% reduction in BACE1 enzyme levels caused only a 12% decrease in A␤ levels in young mice, it nonetheless resulted in a dramatic reduction in A␤ plaques, neuritic burden, and synaptic deficits in older mice. Quantitative analyses indicate that brain A␤ levels in young APP transgenic mice are not the sole determinant for the changes in plaque pathology mediated by reduced BACE1. These observations demonstrate that partial reductions of BACE1 enzyme activity and concomitant A␤ levels lead to dramatic inhibition of A␤-driven AD-like pathology, making BACE1 an excellent target for therapeutic intervention in AD.Alzheimer disease is the major cause of dementia in elderly people and is characterized by progressive cognitive decline. There is no cure, current treatments offer only temporary relief, and death invariably ensues. Substantial evidence suggests that the amyloid ␤ peptide (A␤) 6 is the cause of Alzheimer disease (AD)-associated neuropathology (1). A␤ is derived by sequential proteolysis of the amyloid precursor protein (APP) through ␤-and ␥-secretase activities and is widely deposited in amyloid plaques in the brains of individuals with AD (2, 3). Therefore, inhibiting the action of one or both of these enzymatic activities may provide inaugural disease-modifying therapies for AD.The aspartyl protease BACE1 is the primary ␤-secretase (4 -6) and is the sole ␤-secretase in mice, since its genetic ablation fully abolishes A␤ generation (7-9). Early reports indicated that BACE1 knock-out animals are healthy and fertile, with no histological pathologies, suggesting that inhibition of BACE1 for therapeutic intervention in AD would have no mechanism related toxicities (7, 9, 10). In contrast, recent reports of partially penetrant lethality and cognitive deficits in BACE1 knock-out animals do suggest potential liabilities of complete BACE1 inhibition (11, 12). As the initiating enzyme in the generation of A␤, BACE1 is a key drug target and would be predicted to abrogate pathologies associated with any form of A␤. To avoid potential side effects re...

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Section: Discussionmentioning

confidence: 99%

Section: Heterozygous Bace1 Gene Knock-out Has a Modest Effect On Solmentioning

confidence: 99%

Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice

McConlogue

Buttini

Anderson

et al. 2007

Journal of Biological Chemistry

277

226

View full text Add to dashboard Cite

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“…These include the development of parenchymal amyloid-␤ (A␤) plaques, neuritic pathology, synaptic loss, and gliosis. A number of reports have shown that active (Schenk et al, 1999;Dickstein et al, 2006) and passive (Bard et al, 2000;Wilcock et al, 2004;Buttini et al, 2005) A␤ immunotherapeutic approaches are effective in reducing or eliminating these pathologies in preclinical studies (Janus et al, 2000;Morgan et al, 2000;Wilcock et al, 2004). In addition, other studies have shown improvement in various cognitive tests (Janus et al, 2000;Morgan et al, 2000;Wilcock et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy Reduces Vascular Amyloid- in PDAPP Mice

Schroeter¹,

Khan²,

Barbour³

et al. 2008

Journal of Neuroscience

117

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In addition to parenchymal amyloid-␤ (A␤) plaques, Alzheimer's disease (AD) is characterized by A␤ in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular A␤ (VA␤) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-A␤ antibodies may clear parenchymal amyloid but increase VA␤ and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VA␤ and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VA␤ and microhemorrhage in PDAPP mice by comparing antibodies with different A␤ epitopes (3D6, A␤ 1-5 ; 266, A␤ 16 -23 ) and performing a 3D6 dose-response study. VA␤ and microhemorrhage were assessed using concomitant A␤ immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VA␤ in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VA␤ was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with A␤ deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VA␤ levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VA␤. These observations raise the possibility that A␤ immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.

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“…Stimulating the production of A␤ antibodies by active immunization with synthetic A␤ (11) or administering monoclonal A␤ antibodies (12,13) reduced amyloid pathology and inflammation and improved cognitive function in mouse models of AD (14). In patients with mild to moderate AD active immunization appears to reduce plaque load (15), and in some patients production of A␤ antibodies correlated with attenuated cognitive decline (16).…”

mentioning

confidence: 99%

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

Britschgi¹,

Olin²,

Johns³

et al. 2009

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

170

163

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A number of distinct ␤-amyloid (A␤) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural A␤-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic A␤ and amyloidogenic non-A␤ species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of A␤ and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of A␤1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant A␤, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from A␤ toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with A␤ the monkeys developed high titers not only against A␤ peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of A␤ antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD. A lzheimer's disease (AD) is the most common cause of dementia, affecting an estimated 5.3 million individuals in the United States alone. Deposits of ␤-amyloid peptide (A␤) in extracellular plaques characterize the AD brain, but soluble oligomeric A␤ species appear to be more neurotoxic than plaques and interfere with synaptic function (reviewed in ref. 1). Notably, most A␤ peptides isolated from AD brains are posttranslationally modified and truncated (2-6), and some are proposed to be oxidized (7,8) or cross-linked at Tyr-10 (9). Although the pathogenic consequences of these modifications need to be resolved, most of them can stabilize A␤ assemblies, interfere with proteolytic degradation, and increase A␤ toxicity in vitro (7,8,10).One line of defense against toxic A␤ species could be neutralizing antibodies. Stimulating the production of A␤ antibodies by active immunization with synthetic A␤ (11) or administering monoclonal A␤ antibodies (12, 13) reduced amyloid pathology and inflammation and improved cognitive function in mouse models of AD (14). In patients with mild to moderate AD active immunization appears to reduce plaque load (15), and in some patients production of A␤ antibodies correlated with attenuated cognitive decline (16). It has also been suggested that antibodies recognizing different domains (12,13,17) or conformations (18, 19) of A␤ may have different efficacy in humans.Interestingly, antibodies agai...

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β-Amyloid Immunotherapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease

Cited by 170 publications

References 43 publications

Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice

Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice

Immunotherapy Reduces Vascular Amyloid- in PDAPP Mice

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

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