The correct figure is displayed here, and the article
has been corrected online. “
“Alzheimer’s disease (AD) is the most common cause of dementia and we do not know as yet how to prevent, slow, or reverse the disease with currently available drugs. Amyloid-β (Aβ) is constantly produced in the brain, predominantly by neurons, and is secreted as a monomer. During most of our life, it click here is cleared and does not build up in the brain. However, in some people that go on to develop AD, it aggregates in the brain to form amyloid plaques and cerebral amyloid angiopathy (CAA). Aβ deposition and the subsequent aggregation of tau culminating in the formation of neurofibrillary tangles are two major pathological hallmarks of AD. By the time humans begin to have the earliest clinical symptoms and signs of AD, the amount of Aβ pathology in the brain is already substantial, probably close to the amount that will be present in the stage of advanced dementia due to AD (Jack et al., 2010; Perrin et al., 2009). Therefore, for those individuals who already have developed amyloid plaques and who are still asymptomatic or have very mild dementia, developing effective therapies that can effectively SAHA HDAC order remove and decrease toxicity of pre-existing plaques and CAA without
causing side effects is a major goal. Many anti-Aβ antibodies are being developed as potential treatments for AD but success has been limited. A murine monoclonal antibody to Aβ, 3D6, was shown in several studies to decrease amyloid plaques and CAA when given soon after Aβ deposition began (Bard et al., 2000; Schroeter et al., 2008). However, results from a recent phase III clinical trial using bapineuzumab (the human equivalent of 3D6) in patients with mild to moderate AD revealed disappointing results, including lack of clinical effects, no evidence of plaque removal (though it appears to have attenuated further increases in plaques), as well as provocation of side effects associated with
CAA including edema and hemorrhages in the brain (Scheltens et al., 2012, Clinical Trials on Alzheimer’s Disease, abstract) (Sperling et al., 2012). It is unclear whether this particular failure in a phase III clinical trial is due to inadequate timing of treatment (i.e., too late), of lack of adequate target engagement, or both. Given that the most effective results on amyloid plaque and CAA removal in animal models have been obtained when anti-Aβ antibodies are started before Aβ pathology is fully formed in the brain (Das et al., 2001), discrepancies between the results from animal models and humans in plaque removal may stem from lack of efficacy of the anti-Aβ antibody being used in regard to its ability to actually remove existing Aβ aggregates. Thus, lack of target engagement along with side effects may have been a real issue with this antibody at the doses used in humans. In this issue of Neuron, DeMattos et al.
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