Bapineuzumab and solanezumab for Alzheimer's disease: is the ‘amyloid cascade hypothesis' still alive?

Tayeb, Haythum O.; Murray, Evan D.; Price, Bruce H.; Tarazi, Frank I.

doi:10.1517/14712598.2013.789856

Cited by 107 publications

(93 citation statements)

References 67 publications

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“…The roles of these O-glycans are elusive, although it has been proposed that APP processing by a-secretase, b-secretase and c-secretase occurs after O-glycosylation of APP, and that O-glycosylated APP is preferentially secreted [26,29]. Interestingly, a recent report demonstrated a new type of tyrosine O-glycosylation on short (Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] to Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] but not on full-length (Ab 1-38 to Ab 1-42 ) Ab fragments [27]. In a study using CSF from AD patients and nondemented controls, an increase in the short Ab fragments carrying the tyrosine-linked glycan was observed in AD patients.…”

Section: App and Glycosylationmentioning

confidence: 99%

The role of protein glycosylation in Alzheimer disease

2013

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Glycosylation is one of the most common, and the most complex, forms of post-translational modification of proteins. This review serves to highlight the role of protein glycosylation in Alzheimer disease (AD), a topic that has not been thoroughly investigated, although glycosylation defects have been observed in AD patients. The major pathological hallmarks in AD are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are composed of phosphorylated tau, and the plaques are composed of amyloid b-peptide (Ab), which is generated from amyloid precursor protein (APP). Defects in glycosylation of APP, tau and other proteins have been reported in AD. Another interesting observation is that the two proteases required for the generation of amyloid b-peptide (Ab), i.e. c-secretase and b-secretase, also have roles in protein glycosylation. For instance, c-secretase and b-secretase affect the extent of complex N-glycosylation and sialylation of APP, respectively. These processes may be important in AD pathogenesis, as proper intracellular sorting, processing and export of APP are affected by how it is glycosylated. Furthermore, lack of one of the key components of c-secretase, presenilin, leads to defective glycosylation of many additional proteins that are related to AD pathogenesis and/or neuronal function, including nicastrin, reelin, butyrylcholinesterase, cholinesterase, neural cell adhesion molecule, v-ATPase, and tyrosine-related kinase B. Improved understanding of the effects of AD on protein glycosylation, and vice versa, may therefore be important for improving the diagnosis and treatment of AD patients.

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Section: App and Glycosylationmentioning

confidence: 99%

The role of protein glycosylation in Alzheimer disease

2013

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“…The most promising current drug candidates are antibodies such as solanezumab that target various Aβ forms [136]. Solanezumab did not improve cognitive function in the two major phase 3 trials [137], but if one analyses the combined data there is a positive effect on cognition that should be explored further [138] [139].…”

Section: (X) Clinical Performancementioning

confidence: 99%

Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease

Kepp

2016

JAD

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The inability to effectively halt or cure Alzheimer's Disease (AD), exacerbated by the recent failures of high-profile clinical trials, emphasizes the urgent need to understand the complex biochemistry of this major neurodegenerative disease. In this paper, ten central, current challenges of the major paradigm in the field, the amyloid hypothesis, are sharply formulated.These challenges together show that new approaches are necessary that address data heterogeneity, increase focus on the proteome level, use available human patient data more actively, account for the aging phenotype as a background model of the disease, unify our understanding of the interplay between genetic and non-genetic risk factors, and combine into one framework both the familial and sporadic forms of the disease.

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“…Although clinical trials of the Aβ-directed mAb Bapinezumab showed no clear cognitive benefits in patients with mild to moderate AD [42], the results also indicated that APOE ε4 carrier status may limit the response to anti-Aβ passive immunization [43,44], as well as being associated with an increased rate of microbleeds and vasogenic edema [45]. As the intention of upcoming clinical trials of Aβ-directed therapeutics is to target patients with early and prodromal AD [46,47], there is still a potential for differential responses to treatment among carriers of various APOE alleles.…”

Section: Discussionmentioning

confidence: 99%

Blocking the apoE/Aß interaction ameliorates Aß-related pathology in APOE ¿2 and ¿4 targeted replacement Alzheimer model mice

Pankiewicz

Guridi

Kim

et al. 2014

Acta Neuropathol Commun

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Accumulation of β-amyloid (Aβ) in the brain is essential to Alzheimer's disease (AD) pathogenesis. Carriers of the apolipoprotein E (APOE) ε4 allele demonstrate greatly increased AD risk and enhanced brain Aβ deposition. In contrast, APOE ε2 allele carries show reduced AD risk, later age of disease onset, and lesser Aβ accumulation. However, it remains elusive whether the apoE2 isoform exerts truly protective effect against Aβ pathology or apoE2 plays deleterious role albeit less pronounced than the apoE4 isoform. Here, we characterized APP SW /PS1 dE9 / APOE ε2-TR (APP/E2) and APP SW /PS1 dE9 /APOE ε4-TR (APP/E4) mice, with targeted replacement (TR) of the murine Apoe for human ε2 or ε4 alleles, and used these models to investigate effects of pharmacological inhibition of the apoE/Aβ interaction on Aβ deposition and neuritic degeneration. APP/E2 and APP/E4 mice replicate differential effect of human apoE isoforms on Aβ pathology with APP/E4 mice showing a several-fold greater load of Aβ plaques, insoluble brain Aβ levels, Aβ oligomers, and density of neuritic plaques than APP/E2 mice. Furthermore, APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on object recognition and radial arm maze tests. Between the age of 6 and 10 months APP/E2 and APP/E4 mice received treatment with Aβ12-28P, a non-toxic, synthetic peptide homologous to the apoE binding motif within the Aβ sequence, which competitively blocks the apoE/Aβ interaction. In both lines, the treatment significantly reduced brain Aβ accumulation, co-accumulation of apoE within Aβ plaques, and neuritic degeneration, and prevented memory deficit in APP/E4 mice. These results indicate that both apoE2 and apoE4 isoforms contribute to Aβ deposition and future therapies targeting the apoE/Aβ interaction could produce favorable outcome in APOE ε2 and ε4 allele carriers.

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Bapineuzumab and solanezumab for Alzheimer's disease: is the ‘amyloid cascade hypothesis' still alive?

Cited by 107 publications

References 67 publications

The role of protein glycosylation in Alzheimer disease

The role of protein glycosylation in Alzheimer disease

Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease

Blocking the apoE/Aß interaction ameliorates Aß-related pathology in APOE ¿2 and ¿4 targeted replacement Alzheimer model mice

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