A small-molecule inhibitor of caspase-1 has a seemingly large effect in a mouse model of Alzheimer’s disease. Researchers led by Andréa LeBlanc of McGill University in Montreal reported in the September 25 Nature Communications that VX-765 reversed memory loss, quelled neuroinflammation, prevented Aβ deposition, and even recouped lost synapses. It is unclear how the drug manages to accomplish all of these tasks. Even so, the findings cast neuroinflammation as a key driver of the AD cascade, the researchers contend. What’s more, VX-765 has an established safety record in previous clinical trials for epilepsy, making it a ready candidate for AD trials.

  • The caspase-1 inhibitor VX-765 reversed memory loss in J20 mice.
  • The drug dampened neuroinflammation and Aβ deposition.
  • It also spared synapses and axons from degenerating

“The paper represents further validation that blocking chronic neuroinflammation is a putative modality to arrest the progression of AD,” commented Matthew Cooper of the University of Queensland in Brisbane, Australia.

The study grew out of a wealth of data implicating a different caspase in a neuroinflammatory cascade in the AD brain. Previously, LeBlanc had correlated caspase-6 in postmortem brain with cognitive decline, placed this protease amidst neuritic plaques and tau tangles, and caught it processing tau into aggregation-prone forms (Albrecht et al., 2007; Guo et al., 2004; Albrecht et al., 2009). Caspase-6 also triggers axonal degeneration and clips a bevy of proteins that support the neuronal cytoskeleton (Feb 2009 news and Klaiman et al., 2008). Alas, no therapeutically viable inhibitors of caspase-6 exist, so LeBlanc looked upstream. She identified caspase-1, which, besides unleashing active interleukins, also activates caspase-6 (Kaushal et al., 2015). 

First author Joseph Flores and colleagues tested VX-765, a blood-brain-barrier-penetrant inhibitor of caspase-1, in J20 transgenic mice, which express human APP carrying the Swedish mutation. To see if the drug would affect memory loss, the researchers injected five-month-old mice three times per week in the abdomen with 50 mg/kg of VX-765 or a placebo. After six weeks, the researchers stopped injections for a “washout period” of four weeks, then resumed treatment for two additional weeks. They tested memory at baseline, after weeks three and six, after washout, and after the final two weeks of injections, and killed the mice at eight months of age to assess neuropathology.

Before their first injection, the J20 mice already flagged on measures of learning and spatial memory, including the novel-object-recognition test and the Barnes maze, and they were hyperactive compared with wild-type. Their performance caught up to wild-type levels between the third and sixth weeks of injections with VX-765, but not placebo. While memory problems re-emerged after the washout, they were alleviated again when treatment resumed. The findings suggested VX-765 rapidly and reversibly affects memory in mice.

Given that caspase-1 stokes inflammation, the researchers next investigated if the inhibitor would affect microglia. At five months, J20 mice already had more cells expressing the microglial activation marker Iba1 than did wild-type mice, and a greater proportion of those cells assumed the amoeba-like shape typical for activated microglia. By the end of the treatment, Iba1+ and amoeboid cell numbers matched those in wild-type, while untreated eight-month-old J20 mice had even more microgliosis than five-month-olds. VX-765-treated mice also had lower hippocampal concentrations of IL-1β, a pro-inflammatory cytokine that is activated when caspase-1 cleaves it.

Plaque Prevention.

Plaques accumulated between five (left) and eight months of age (middle) in J20 mice, but not in mice treated with VX-765 (right). [Courtesy of Flores et al., Nature Communications, 2018.]

Would the inhibitor affect Aβ deposition? To their surprise, Flores and colleagues found that at eight months, VX-765-treated mice had a lower Aβ plaque burden than untreated mice. In hippocampal and cortical extracts, the ratio of soluble Aβ42 to soluble Aβ38/40/42 was roughly halved, though total Aβ and APP did not change. LeBlanc told Alzforum that while she does not know how VX-765 dampens Aβ deposition, she assumes that it alleviates inflammation and neuronal stress.

The researchers confirmed caspase-1’s involvement in neuroinflammation and Aβ deposition by crossing caspase-1-deficient mice to the J20 animals. For the most part, their findings in caspase-1 knockouts meshed with those from the VX-765-treated animals.

Finally, the researchers looked at synaptic deficits. At baseline, the J20 mice already had low hippocampal levels of the synaptic marker synaptophysin. By eight months, synaptophysin remained low in control mice, but had risen to normal levels in treated mice.

Synapses Bounce Back? In the hippocampi of J20 mice, synaptophysin (brown) was low at five (left) and lower still at eight months (second panel). In VX-765-treated mice, synaptophysin increased to wild-type levels. [Courtesy of Flores et al., Nature Communications, 2018.]

All told, the data suggested that VX-765’s effects on neuroinflammation, Aβ accumulation, and synaptic loss culminate in a reversal of memory loss in the J20 mice. LeBlanc hypothesized that VX-765’s benefits stem from its ability to block caspase-1 from cleaving caspase-6, and she is developing caspase-6-deficient AD models to test the idea.

LeBlanc told Alzforum that VX-765, developed by Vertex Pharmaceuticals, has now been licensed to another company. She is involved in discussions with that company to develop the drug for treatment of AD, LeBlanc said.

Cooper cautioned that VX-765’s side effects in prior trials of epilepsy patients—dizziness being the most common—made it likely unsuitable for a chronic condition such as AD. LeBlanc countered that the doses in the epilepsy trial were higher than the human equivalent doses of VX-765 she used in the mouse study.

Cooper is developing inhibitors against the NLRP3 inflammasome, another activator of caspase-1, which he thinks may be more selective (Coll et al., 2015; Dempsey et al., 2017). Several biotech and pharmaceutical companies are also targeting the same inflammasome, said Cooper. “It remains to be seen if NLRP3 inhibitors will be safer than VX-765,” he wrote. David Brough of the University of Manchester, England, U.K., who is studying NLRP3 inhibitors, said LeBlanc’s data further support the involvement of inflammasome pathways in neurodegenerative disease and their potential for therapeutic targeting (Sep 2017 news). 

LeBlanc added that the NLRP3-caspase-1 pathway is only active in glial cells, whereas the Caspase-1/Caspase-6 pathway, which is triggered by NLRP1, is primarily active in degenerating neurons.—Jessica Shugart


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News Citations

  1. Keystone: Death Receptor Ligand—New Role for APP, New Model for AD?
  2. New AD Target: Silencing the NLRP3 Inflammasome with Boron?

Research Models Citations

  1. J20 (PDGF-APPSw,Ind)

Paper Citations

  1. . Activation of caspase-6 in aging and mild cognitive impairment. Am J Pathol. 2007 Apr;170(4):1200-9. PubMed.
  2. . Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease. Am J Pathol. 2004 Aug;165(2):523-31. PubMed.
  3. . Caspase-6 activation in familial alzheimer disease brains carrying amyloid precursor protein or presenilin i or presenilin II mutations. J Neuropathol Exp Neurol. 2009 Dec;68(12):1282-93. PubMed.
  4. . Targets of caspase-6 activity in human neurons and Alzheimer disease. Mol Cell Proteomics. 2008 Aug;7(8):1541-55. PubMed.
  5. . Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ. 2015 Oct;22(10):1676-86. Epub 2015 Mar 6 PubMed.
  6. . A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015 Mar;21(3):248-55. Epub 2015 Feb 16 PubMed.
  7. . Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017 Mar;61:306-316. Epub 2016 Dec 18 PubMed.

Further Reading


  1. . Familial amyloid precursor protein mutants cause caspase-6-dependent but amyloid β-peptide-independent neuronal degeneration in primary human neuron cultures. Cell Death Dis. 2010 Nov 18;1:e100. PubMed.
  2. . A caspase cascade regulating developmental axon degeneration. J Neurosci. 2012 Dec 5;32(49):17540-53. PubMed.
  3. . Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?. SLAS Discov. 2018 Dec;23(10):991-1017. Epub 2018 Jul 3 PubMed.
  4. . Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9593-8. Epub 2016 Aug 1 PubMed.
  5. . Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9587-92. Epub 2016 Aug 1 PubMed.

Primary Papers

  1. . Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model. Nat Commun. 2018 Sep 25;9(1):3916. PubMed.