Blocking the Harmful Behavior of a Key Alzheimer’s Enzyme

Enzymes rarely have one job. So, attempts to shut down the enzyme that causes the hallmarks of Alzheimer’s disease often mean side effects, because these therapies prevent the enzyme from carrying out many other functions. A study appearing February 25 in Cell Reports presents a new therapeutic strategy: blocking the most harmful behavior enzyme while allowing it to work normally otherwise. This potential approach now needs to be further developed and tested in pre-clinical trials.

In the brains of patients with Alzheimer’s disease (AD), amyloid precursor protein is broken apart, and the resulting fragments–β-amyloid peptides, or Aβ peptides–aggregate to form plaques. Aβ peptides are produced by the action of two enzymes called beta- and gamma-secretases. Inhibiting either of these enzymes would block the production of toxic Aβ peptides; however, attempts to inhibit gamma-secretase caused problems in clinical trials because the enzyme also cleaves more than 20 other proteins important for normal physiology. β-secretase is now considered an alternative therapeutic target for AD, and a wide variety of inhibitors have been developed; however, β-secretase also cleaves several other proteins with normal functions in the body.

In their latest research, Lawrence Rajendran, of the University of Zurich in Switzerland, and his colleagues discovered that, unlike non-amyloid proteins, the Alzheimer’s-associated amyloid precursor protein is cleaved by β-secretase in membrane-bound compartments inside cells, called endosomes. Exploiting this compartmentalization, the team developed an endosomally-targeted β-secretase inhibitor that specifically blocked cleavage of amyloid precursor protein but not non-amyloid proteins. This is the first time such specificity has been achieved, and it thus provides a potentially promising way to treat AD without causing major side effects.

Diagram shows how the drugs will target BACE1.
This visual abstract depicts how Ben Halima et al. demonstrate the feasibility of designing drugs targeting the Alzheimer-related enzyme BACE1 without affecting its physiological function. Using structural, biochemical, and cellular approaches, they show that BACE1 inhibitors can be designed to specifically inhibit its disease-causing activity, enhancing their potential as therapeutics without undesired side effects. Credit: Ben Halima et al./Cell Reports 2016.

“The current β-secretase inhibitors inhibit both the Alzheimer’s disease process and physiologically relevant processes, and this would be a major problem, similar to the gamma-secretase inhibitors that failed in the clinic; however, with our strategy, we now can specifically inhibit the Alzheimer’s process thereby avoiding any side effects,” says Rajendran. He and his team plan to develop this inhibitor further and test it in clinical trials.

About this Alzheimer’s disease research

Funding: The authors acknowledge financial support from the Swiss National Science Foundation, the Velux Foundation, the Cure Alzheimer Fund, the Baugarten Stiftung, and the German Federal Ministry for Education and Research.

Source: Joseph Caputo – Cell Press
Image Credit: Image is credited to Ben Halima et al./Cell Reports 2016.
Original Research: Full open access research for “Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein” by Saoussen Ben Halima, Sabyashachi Mishra, K. Muruga Poopathi Raja, Michael Willem, Antonio Baici, Kai Simons, Oliver Brüstle, Philipp Koch, Christian Haass, Amedeo Caflisch, and Lawrence Rajendran in Cell Reports. Published online February 25 2016 doi:10.1016/j.celrep.2016.01.076


Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein

•The AD-linked protease BACE1 cleaves APP to produce toxic β-amyloid peptides
•BACE1 also cleaves the non-amyloid substrates NRG1 and L1
•BACE1 cleavage of NRG1 and L1 is endocytosis-independent, unlike the cleavage of APP
•The endosomally targeted BACE1 inhibitor spares NRG1 and L1 but inhibits APP processing

Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic β-amyloid (Aβ) peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit β-cleavage of non-amyloid substrates like Neuregulin. We report that β-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of β-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by β-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal β-secretase by an endosomally targeted β-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. β-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects.

“Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein” by Saoussen Ben Halima, Sabyashachi Mishra, K. Muruga Poopathi Raja, Michael Willem, Antonio Baici, Kai Simons, Oliver Brüstle, Philipp Koch, Christian Haass, Amedeo Caflisch, and Lawrence Rajendran in Cell Reports. Published online February 25 2016 doi:10.1016/j.celrep.2016.01.076

Feel free to share this neuroscience news.
Join our Newsletter
I agree to have my personal information transferred to AWeber for Neuroscience Newsletter ( more information )
Sign up to receive our recent neuroscience headlines and summaries sent to your email once a day, totally free.
We hate spam and only use your email to contact you about newsletters. You can cancel your subscription any time.
  1. HYPOTHESIS : PREVENTING AND TREATING SIMULTANEOUSLY THE “DOUBLE HIT” OF AD: (preventing and treating at the same the tau and betamyloid accumulation).

    Professor Robert Vassar (the researcher that discovered the BACE function) and colleagues reported that in AD , “UPSTREAMS” , THE BRAIN ENERGY DEPRIVATION , STARTED FOR EXAMPLE , BY VASCULAR AGEING (leading to disorders in glucose transport and metabolization, and to mitochondrial disorders,etc) , CAN LEADS , “DOWNSTREAMS”, TO INCREASES THE BACE1 LEVELS , INCREASING BETAMYLOID ACCUMULATION IN THE BRAINS of the transgenic mouse model of AD.

    Then, using our RATIONAL THINKING , if “UPSTREAMS”, the Brain Energy Deprivation (by impairments of glucose metabolization caused by peroxinitrites accumulation, that leads to mitochondrial disfunction, etc), Leads to BACE Accumulation , and if the pharma companies, Instead to Search , ” DOWNSTREAMS”, for BACE INHIBITORS, using the logical reasoning , if they use supplements and drugs to Treat the metabolical, molecular and biochemical disorders that leads to the Brain Energy Deprivation (that is the responsible to increase of BACE ), they will control the BACE Accumulation, without no need of BACE INHIBITORS.

    Lowering peroxinitrites accumulation will improves mitochondrial function, and associating to substances that are mitochondrial function improvers and that are antiglycating, and works as alternative fuels to the neurons, they will increases the brain energy.

    But “mysteriously”, most big pharma companies are searching for drugs to treat the Lasts Steps of neurodegeneration : they are searching for BACE inhibitors …

    And what about TAU ACCUMULATION triggered by Brain Energy Deprivation ?

    As we can see bellow , the Chronic Brain Energy Deprivation leads to TAU ACCUMULATION too (so called tau tangles inside the neurons),as dozens of research articles proved.


    In the article published in march 2006, in the prestigeous american Journal of Alzheimer Disease ,by the authors Iqbal and colleagues , with the title :

    ” Impaired Brain Glucose Metabolism Leads to Alzheimer Neurofibrillary Degeneration (tau tangles) Through a Decrease in Tau O-GlcNAcylation” , we can read that :

    ” It is well established that BRAIN GLUCOSE UPTAKE /METABOLISM IS IMPAIRED IN AD” and that ” the impaired glucose uptake/metabolism contributes to Alzheimer Disease by facilitating abnormal HYPERPHOSPHORYLATION (leading to accumulation) OF TAU .”

    Then , researchers knows very well that TREATING the disorders that leads to Brain Energy Starvation (in some cases called Neuroglycopenia by metabolical and mytochondrial disfunction in the neurons ), as treating the peroxinitrites accumulation, mytochondrial disfunction,etc., with peroxinitrites scavengers, mytochondrial improvers, alternative fuels to the neurons ,they will prevent and treat “UPSTREAMS ” AD and others dementias, years before, “SOWNSTREAMS” any tau or betamyloid accumulation ,and will lowers substantially such accumulations too.

    OK, if pharma companies try to treat the Lasts Steps, but Not the Firsts Steps of a disease, the pharma companies will keeps a high number of patients in the Lasts Steps of it disease, leading to huge costs, keeping a very low efficacy to control the disease . (Hummm, good to bigpharma and bad to patients? I do not believe in None way that big pharma could do it to the “poor” dementia patients.)

    I prefer to believe that big pharma still Not realized that Treating “UPSTREAMS” the Brain Energy Deprivation (caused by impairments in glucose metabolization) , they will Prevent and Treat “DOWNSTREAMS” ,BOTH , the BACE overproduction (preventing and treating Betamyloid Accumulation) and at the same time the TAU Accumulation (preventing and treat “tau tangles”).

    And as is well known, to gives lots of glucose to the patient will Not works to increases brain energy, and can be Toxic , once the problem is Not how much glucose the ´patient has in his brain : the problem is that the neurons can Not metabolizes glucose to ATP (can Not do energy from glucose, as we can see bellow).

    As Hundreds of research articles shows, the Molecular, Metabolical, Biochemical Neurons Disorders that leads to Brain Energy Deprivation (disorders that impairs the brain glucose metabolism to form ATP) , are the : peroxinitrites accumulation, mitochondrial disorders, glycation, heavy metal accumulation ,that leads to neuroinflammation , that after years of a vicious circle of such disorders it leads , “Downstreams” to BACE accumulation.

    And as we can read in the article published in the Az Forum in 2 may 2015 with the title,
    ” Do Extended Species of Aβ Poison Synapses, Masquerade As Dimers? ” , professor doctor ” Vivian Hook at the University of California, San Diego, wrote to Alzforum :

    ” BACE1 INHIBITORS COULD BE DETRIMENTAL TO AD PATIENTS, because an increase in Neurotoxic NTE-Betamyloid May Reduce Memory Function.”

    Then , again , the Rational Thinking based in scientific findings shows that to try to treat betamyloid accumulation “downstreams” with BACE INHIBITORS , IS AN ABSOLUTE AND VERY TOXIC NONSENSE …

    I guess that it is time to finish this “long goodbye” to the flawed hypothesis of Aβ as the cause of AD. After these long 30 years of failures in research based on a flawed hypothesis of oligomers, Aβ, and tau accumulation. As we are seeing now, that flawed hypothesis led to dollars spent without a consistent result.

    It is time to “think big” about new ways for research to find drugs that can enhance micro- and macrovascular brain function, reduce the high oxidative stress in the neurons, and enhance mitochondrial function and energy supply to the neurons. Maybe then we will be able to prevent and treat Aβ disorders.


Comments are closed.