Article

Tau-targeted treatment strategies in Alzheimer's disease

Alzheimer's and Parkinson's Disease Laboratory, Brain & Mind Research Institute, University of Sydney, Camperdown, NSW, Australia.
British Journal of Pharmacology (Impact Factor: 4.99). 11/2011; 165(5):1246-59. DOI: 10.1111/j.1476-5381.2011.01713.x
Source: PubMed

ABSTRACT With populations ageing worldwide, the need for treating and preventing diseases associated with high age is pertinent. Alzheimer's disease (AD) is reaching epidemic proportions, yet the currently available therapies are limited to a symptomatic relief, without halting the degenerative process that characterizes the AD brain. As in AD cholinergic neurons are lost at high numbers, the initial strategies were limited to the development of acetylcholinesterase inhibitors, and more recently the NMDA receptor antagonist memantine, in counteracting excitotoxicity. With the identification of the protein tau in intracellular neurofibrillary tangles and of the peptide amyloid-β (Aβ) in extracellular amyloid plaques in the AD brain, and a better understanding of their role in disease, newer strategies are emerging, which aim at either preventing their formation and deposition or at accelerating their clearance. Interestingly, what is well established to combat viral diseases in peripheral organs - vaccination - seems to work for the brain as well. Accordingly, immunization strategies targeting Aβ show efficacy in mice and to some degree also in humans. Even more surprising is the finding in mice that immunization strategies targeting tau, a protein that forms aggregates in nerve cells, ameliorates the tau-associated pathology. We are reviewing the literature and discuss what can be expected regarding the translation into clinical practice and how the findings can be extended to other neurodegenerative diseases with protein aggregation in brain.

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    ABSTRACT: Immunotherapy is currently being intensively explored as much-needed disease-modifying treatment for neurodegenerative diseases. While Alzheimer's disease (AD) has been the focus of numerous immunotherapeutic studies, less attention has been paid to Parkinson's disease (PD) and other neurodegenerative disorders. The reason for this difference is that the amyloid beta (Aβ) protein in AD is a secreted molecule that circulates in blood and is readably recognized by antibodies. In contrast, α-synuclein (α-syn), tau, huntingtin and other proteins involved in neurodegenerative diseases have been considered to be exclusively of intracellular nature. However, the recent discovery that toxic oligomeric versions of α-syn and tau accumulate in the membrane and can be excreted to the extracellular environment has provided a rationale for the development of immunotherapeutic approaches for PD, dementia with Lewy bodies, frontotemporal dementia, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins. Active immunization, passive immunization, and T cell-mediated cellular immunotherapeutic approaches have been developed targeting Aβ, α-syn and tau. Most advanced studies, including results from phase III clinical trials for passive immunization in AD, have been recently reported. Results suggest that immunotherapy might be a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and propagation of toxic protein aggregates. In this manuscript we provide an overview on immunotherapeutic advances for neurodegenerative disorders, with special emphasis on α-synucleinopathies.
    Pharmacology [?] Therapeutics 02/2013; 138(3). DOI:10.1016/j.pharmthera.2013.01.013 · 7.75 Impact Factor

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