Advances in the therapy of Alzheimer’s disease: targeting amyloid beta and tau and perspectives for the future

Hampel, Harald; Schneider, Lon S.; Giacobini, Ezio; Kivipelto, Miia; Sindi, Shireen; Dubois, Bruno; Broich, Karl; Nisticò, Robert; Aisen, Paul S.; Lista, Simone

doi:10.1586/14737175.2015.995637

Cited by 67 publications

(59 citation statements)

References 150 publications

(125 reference statements)

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“…Furthermore, small molecules belonging to TAIs have already been developed and tested in humans [29,34,35], even if with discrepancy between the cell-based and/or in vitro data and the in vivo efficacy. Important pharmaceutical implications have been rising from the possibility to distinguish the tau-tau binding interaction from the tautubulin binding one with new aggregation inhibitors [36,37].…”

Section: Tau Aggregation Inhibitormentioning

confidence: 99%

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

Pietrobono¹,

Giacomelli²,

Ml³

et al. 2017

Glob Drugs Therap

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Section: Tau Aggregation Inhibitormentioning

confidence: 99%

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

Pietrobono¹,

Giacomelli²,

Ml³

et al. 2017

Glob Drugs Therap

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“…Another approach is passive immunization, which has the advantage to bypass T-cell engagement and allow a better control of monoclonal antibody (mAb) dosage and epitope targeting. However, recent phase III AD trials of two anti-Aβ mAbs, solanezumab and bapineuzumab, failed to slow cognitive or functional decline in patients with mild-tomoderate AD (10). The main argument put forward to explain the lack of efficacy of these passive immunization approaches was that treatment might have started too late to reverse or delay the disease process (11).…”

Section: Introductionmentioning

confidence: 99%

A Modification-Specific Peptide-Based immunization Approach Using CRM197 Carrier Protein: Development of a Selective Vaccine Against Pyroglutamate Aβ Peptides

Zhao

Chandakkar

Acker

et al. 2016

Mol Med

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Strategies aimed at reducing cerebral accumulation of the amyloid-β (Aβ) peptides have therapeutic potential in Alzheimer's disease (AD). Aβ immunization has proven to be effective at promoting Aβ clearance in animal models but adverse effects have hampered its clinical evaluation. The first anti-Aβ immunization clinical trial, which assessed a full-length Aβ1-42 vaccine, increased the risk of encephalitis most likely because of autoimmune pro-inflammatory T helper 1 (Th1) response against all forms of Aβ. Immunization against less abundant but potentially more pathologically relevant Aβ products, such as N-terminally-truncated pyroglutamate-3 Aβ (AβpE3), could provide efficacy and improve tolerability in Aβ immunotherapy. Here, we describe a selective vaccine against AβpE3, which uses the diphtheria toxin mutant CRM197 as carrier protein for epitope presentation. CRM197 is currently used in licensed vaccines and has demonstrated excellent immunogenicity and safety in humans. In mice, our AβpE3:CRM197 vaccine triggered the production of specific anti-AβpE3 antibodies that did not cross-react with Aβ1-42, non-cyclized AβE3, or N-terminally-truncated pyroglutamate-11 Aβ (AβpE11). AβpE3:CRM197 antiserum strongly labeled AβpE3 in insoluble protein extracts and decorated cortical amyloid plaques in human AD brains. AntiAβpE3 antibodies were almost exclusively of the IgG1 isotype, suggesting an anti-inflammatory Th2 response bias to the AβpE3:CRM197 vaccine. To the best of our knowledge, this study shows for the first time that CRM197 has potential as a safe and suitable vaccine carrier for active and selective immunization against specific protein sequence modifications or conformations, such as AβpE3.

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“…At present, researchers are emphasising on therapeutic progress in AD delaying disease development and progression that would significantly decrease the mounting global burden. The growing research has led to generation of newer compounds for early-stage of AD; having an absolute impact on the advancement of clinical trial designs in population which are at pre-and asymptomatic risk stages of AD (Hampel et al, 2015).…”

Section: Introductionmentioning

confidence: 99%