New target for Alzheimer’s: APP-C31 under investigation

S_5689_Alzheimer_iS474202902_s700x247

A dementia diagnosis can be devastating – not only for the person with the disease, but also for their loved ones. For people who have never experienced dementia, forgetfulness might be interpreted as an endearing sign of seniority, but after a certain stage at which a person may not remember familiar people, their surroundings, or even the passage of time – the situation can become serious.

Current statistics show that worldwide nearly 44 million people have Alzheimer’s disease (AD) or a related dementia and only 1 in 4 people with AD have been diagnosed. There are currently no established treatments that slow the advancement of this disease; however, a recent study using a chemical-genetics approach to identify inhibitors of amyloid precursor protein (APP) caspase cleavage, is offering new hope for the development of novel AD therapeutics (1).

Under investigation: high-throughput screening against new targets for an AD drug

Pathologically, AD is a progressive neurodegenerative disease characterized by two types of lesions in the brain: extracellular senile plaques and intracellular neurofibrillary tangles (1). Amyloid β-protein is the main constituent of senile plaques and is well known to be generated from APP. Interestingly, APP also gives rise to another cytotoxic fragment when cleaved by caspases: C-terminal 31-amino acid peptide (APP-C31). Both caspase-cleaved APP and activated caspase-9 have been identified in the brains of AD patients, but not in controls (2). More recently, using a murine model, Poksay et al. (2017) showed that a mutation in the cleavage site of APP prevents APP-C31 generation and results in reduced synaptic loss and improved synaptic transmission and spatial memory (1). Following this, they were interested in finding small molecules that inhibit APP cleavage.

As well as C31, another fragment is generated with APP is cleaved: APPΔC31. By using an APPΔC31-specific antibody, they were able to screen several compound libraries and develop an ELISA to validate hit compounds that inhibit APP cleavage. Several inhibitors were discovered, mostly belonging to three different classes involved in regulating calcium: SERCA inhibitors (sarco/endoplasmic reticulum Ca2+ ATPase), inhibitors of Wnt signaling and calcium channel antagonists. Although more work is needed to validate the efficacy of these lead compounds, studies like this are bringing us one step closer to understanding AD and offering new therapeutic approaches for altering the course of disease at the early stage.

In search of new approaches

Studying neurological disorders such as AD often requires optimized assays. We offer PCR arrays, miRNA analysis or pathway reporters for reliable gene expression and regulation studies. If you’re more interested in PCR and qPCR, you can check out our portfolios based on your detection method of choice (intercalating dyes or nucleic acid probes). If you’re not sure which detection method would suit your research, download our new application note comparing the advantages of SYBR Green- and probe-based qPCR methods for different applications and assay types.

References:

  1. 1) Paksay, K.S. et al. (2017) Screening for small molecular inhibitors of statin-induced APP C-terminal toxic fragment production. Front. Pharmacol. 8:46. doi: 10.3389/fphar.2017.00046
  2. 2) Lu, D.C. et al. (2000) A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nat. Med. 6, 397–404. 10.1038/74656 (link)
Laura Alina Mohr, M.Sc.

Laura Alina Mohr joined QIAGEN in 2015. She received her Master’s Degree in Chemical Biology at the Technical University Dortmund in Germany. During this time, she was involved in Systemic Cell Biology research at the prestigious Max Planck Institute. Before joining QIAGEN, Laura Alina worked at the Scripps Research Institute, San Diego, where she first focused on DNA damage/repair pathways and telomere biology. Later, she joined the Muscle Development, Aging and Regeneration program at the Sanford Burnham Prebys Medical Discovery Institute. At QIAGEN she is interested in gene expression profiling focusing on various biological pathways, e.g. cancer research and neurodegeneration.

Your email address will not be published. Required fields are marked *