Merck’s compound has been in the clinic for some years now, and they started the current trial in 2012, with Update: turns out that the 2019 readout is for the early stage (prodromal) patient trial. The mild-to-moderate AD patient trial is getting a first readout next year. Lilly and AstraZeneca have reporting around that time, and yeah, that’s the timeline for Alzheimer’s in the clinic, all right. So this paper is still an early report of a work in progress. What they’re showing is that verubecestat does indeed reduce cleaved amyloid species in rats and monkeys, without evidence of the severe tox liabilities mentioned above. (There was some fur depigmentation seen in the rats, but nothing of the sort in the monkeys). And in humans, the trend continues: the compound reduces amyloid fragments in the CSF of both the control group patients and those with diagnosed Alzheimer’s disease.
Polymorphic variation in the apolipoprotein E (apoE) gene is the major genetic susceptibility factor for late-onset Alzheimer's disease (AD) and likely contributes to neuropathology through various pathways. It is also recognized that apoE undergoes proteolytic cleavage in the brain and the resultant apoE fragments likely have a variety of bioactive properties that regulate neuronal signaling and may promote neurodegeneration. ApoE fragmentation in the human brain has been intensively studied using different immunochemical methods, but has never been analyzed in a quantitative manner to establish preferably accumulated fragments. Here we report quantification using multiple reaction monitoring mass spectrometry (MRM MS) with 15N-labeled full-length apoE4 as an internal standard. Measurements were performed on frontal cortex from control and severe AD donors. Our data point to a preferable accumulation of C-terminal apoE fragment in the insoluble fraction of tissue homogenate in the severe AD group versus the control group. Further insight into the biological consequences of this accumulation may lead to a better understanding of the basic mechanism of AD pathology.
Another recorrection. Mutations that lead to an excess amount of the amyloid precursor protein can increase g protein signalling leading to apoptosis, but this signalling is amplified by the subsequent formation of c terminal fragments of the amyloid precursor protein. Other amyloid precursor protein mutations make the amyloid precursor protein more susceptible to the cleavage that leads to c terminal fragments and this is what contributes to the onset of Alzheimer’s disease in those cases.
“The Alzheimer amyloid precursor protein (APP) is a transmembrane protein whose abnormal processing is associated with the pathogenesis of Alzheimer’s disease. Activated caspases cleave APP and generate its carboxyl-terminally truncated fragment (APPDeltaC31)…These results suggest that accumulation of wild-type APP activates neuronal caspase-3 to generate APPDeltaC31 that mediates caspase-3-independent cell death.”
This would seem to be good news for the developers of BACE inhibitors to treat Alzheimer’s disease, but not really. Amyloid precursor protein production decreases as Alzheimer’s progresses so inhibiting BACE would make little difference. Secondly oxidative stress is only partly dependent upon the c-terminal fragment of the amyloid precursor protein. If you lower oxidative stress by limiting the formation of the c-terminal fragment of the amyloid precursor protein through BACE inhibition, you can perhaps delay the onset of Alzheimer’s disease. If you lessen oxidative stress–no matter what its source–you delay the onset of Alzheimer’s disease and treat it.
Neuregulin-1 (NRG1) plays important roles in the development and plasticity of the brain, and it is also reported to have potent neuroprotective properties. We previously reported that NRG1 has neuroprotective actions against Swedish amyloid precursor protein–induced neurotoxicity. In addition to the amyloid beta peptide, other metabolites of amyloid precursor protein (APP) such as the C-terminal fragments of APP (APP-CTs) have been reported to possess cytotoxic effects in neuronal cells. In this study, we investigated whether NRG1 exerts neuroprotective effects against APP-CTs and attempted to determine its neuroprotective mechanisms. NRG1 attenuated the neurotoxicities induced by the expression of APP-CTs in neuronal cells. NRG1 also reduced the accumulation of reactive oxygen species and attenuated mitochondrial membrane potential loss induced by APP-CTs. In addition, NRG1 upregulated the expression of the anti-apoptotic protein Bcl-2. This effect was blocked by the inhibition of ErbB4, a key NRG1 receptor. Taken together, these results demonstrate the neuroprotective potential of NRG1 in Alzheimer’s disease.
Here is another potential issue. The c-terminal fragment of the amyloid precursor protein (the one produced by the beta secretase) increases g protein signalling and consequent nitro-oxidative stress in Alzheimer’s disease but so too does excessive amounts of the amyloid precursor protein itself. So as pointed out to me last time, mutations that only lead to excess production of the amyloid precursor protein in themselves cause Alzheimer’s disease. Would cutting off the cleavage of the amyloid precursor protein lead to the same result?
Tau is a highly soluble protein, yet it aggregates abnormally in Alzheimer's disease. Here, we address the question of proteolytic processing of tau and the nucleation of aggregates by tau fragments. We show in neuronal cell models that fragments of the repeat domain of tau containing mutations of FTDP17 (frontotemporal dementia with parkinsonism linked to chromosome 17), produced by endogenous proteases, can induce the aggregation of full-length tau. Fragments are generated by successive cleavages, first N-terminally between K257 and S258, then C-terminally around residues 353–364; conversely, when the N-terminal cleavage is inhibited, no fragmentation and aggregation takes place. The C-terminal truncation and the coaggregation of fragments with full-length tau depends on the propensity for β-structure. The aggregation is modulated by phosphorylation but does not depend on it. Aggregation but not fragmentation as such is toxic to cells; conversely, toxicity can be prevented by inhibiting either aggregation or proteolysis. The results reveal a novel pathway of abnormal tau aggregation in neuronal cells.
University of Texas, August 2017
Curcumin combined with other nutrients has anti-cancer properties. The researchers first tested 142 natural compounds on mouse and human cell lines to see which inhibited prostate cancer cell growth when administered alone or in combination with another nutrient. The most promising active ingredients were then tested on model animals: ursolic acid, a waxy natural chemical found in apple peels and rosemary; curcumin, the bright yellow plant compound in turmeric; and resveratrol, a natural compound common to red grapes or berries. “These nutrients have potential anti-cancer properties and are readily available,” says Tiziani. “We only need to increase concentration beyond levels found in a healthy diet for an effect on prostate cancer cells.” The new research paper also demonstrates how the plant-based chemicals work together. Combining ursolic acid with either curcumin or resveratrol prevents cancer cells from gobbling something that they need to grow, glutamine. This is a neat solution: blocking the uptake of a nutrient needed by prostate cancer cells with nutrients that are commonly in the human diet.