Membrane proteolysis in pathogenesis of Alzheimer’s disease: friend or foe?
Membrane proteolytic events are fundamental to the pathogenesis of Alzheimer’s disease (AD) and yet targeting these events has, to date, failed to produce any successful therapeutics. A number of factors underly these failures. These include the multiple physiological roles of the protease targets, late stage of clinical trials and toxicity of drugs developed. The amyloid cascade hypothesis formulated over 25 years ago has underpinned much of the subsequent research and AD drug development but has come under increasing pressures from lack of clinical success. Identification of new AD‑related genes and biochemical pathways, such as intracellular trafficking, immunity and inflammatory cascades has also re‑oriented the focus of current research. Yet still the amyloid hypothesis, initiated by two-stage membrane proteolysis of the amyloid precursor protein (APP) by β‑ and γ‑secretases, remains centre stage. The existence of multiple disease-promoting mutations in the APP gene, and of corresponding protective mutations, still highlights its relevance. The mechanistics of the primary proteolytic events in producing the neurotoxic amyloid β‑peptides will be featured and current developments summarized. The significance of the alternative APP transcripts (APP695,751 and 770) will also be highlighted. Another major focus of development of anti-amyloid therapeutics has been peptide clearance both by proteolysis (e.g. by neprilysin (NEP), insulin-degrading enzyme etc.) and by transport mechanisms (e.g. ApoE, transthyretin (TTR)). Both NEP and TTR are subject to similar epigenetic regulation and manipulation of epigenetic pathways may also provide novel therapeutic targets e.g. selective inhibition of histone deacetylases (HDACs), or other protease activation strategies. In summary, membrane proteases have both neurodegeneration-promoting and neuroprotective roles and can act as friend or foe in the fight against AD. The future still remains optimistic for successful AD therapeutics despite a decade of setbacks. FINANCIAL SUPPORT: This work was supported by Alzheimer’s Research UK and UK Medical Research Council.