On Targeting Secretase in Alzheimer's Disease

The slow progress towards viable therapies for Alzheimer's disease based on clearance of β-amyloid, such as via immunotherapy, has led to a broadening of approaches. Many research groups are looking at other theories on causative mechanisms and other targets for the development of treatments:

Alzheimer's disease (AD) is the most common form of dementia in the elderly and its prevalence is set to increase rapidly in coming decades. However, there are as yet no available drugs that can halt or even stabilize disease progression. One of the main pathological features of AD is the presence in the brain of senile plaques mainly composed of aggregated β amyloid (Aβ), a derivative of the longer amyloid precursor protein (APP). The amyloid hypothesis proposes that the accumulation of Aβ within neural tissue is the initial event that triggers the disease. Here we review research efforts that have attempted to inhibit the generation of the Aβ peptide through modulation of the activity of the proteolytic secretases that act on APP and discuss whether this is a viable therapeutic strategy for treating AD.

From the information reviewed here it remains far from certain whether targeting the secretases involved in APP processing will yield the ground breaking therapeutic that is urgently required to treat AD. The number of high-profile failures in recent years has severely impacted the confidence of large pharmaceutical companies in the continuation of research and development programs in the neuroscience area and a number of companies have scaled back their risk in this field. Further high profile clinical failures could potentially result in the withdrawal of major pharmaceutical companies from the funding of anti-Aβ clinical trials.

The amyloid hypothesis has now been the mainstay of therapeutic research in Alzheimer's disease for over two decades, but a number of issues have plagued the amyloid hypothesis since its inception. First, the level of Aβ burden does not often correlate with clinical manifestation of the disease. Second, the difficulty in isolating the specific neurotoxic species of Aβ and characterizing its effects makes research problematic. Further criticism of the evidence underpinning the amyloid hypothesis revolves around the current transgenic mouse models of AD, which do not fully recapitulate the disease. Despite increased Aβ deposition in these models, there appears to be a lack of coincidental neuronal loss. This is thought to be due mainly to species differences in neuronal susceptibility to Aβ accumulation, a lack of the human tau protein in mice, as well as the lack of a human-like inflammatory response which also plays a pivotal role in the progression of the disease.

Link: http://www.future-science.com/doi/full/10.4155/fso.15.9


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