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Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, et al. Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer’s disease. LeBlanc A, Liu H, Goodyer C, Bergeron C, Hammond J. Involvement of caspases in proteolytic cleavage of Alzheimer’s ß-amyloid precursor protein and amyloidogenic ß-peptide formation. Gervais F, Xu D, Robertson G, Vaillancourt J, Zhu Y, Huang J, et al. Identification of Caspase-6-mediated processing of the valosin containing protein (p97) in Alzheimer’s disease: a novel link to dysfunction in ubiquitin proteasome system-mediated protein degradation. Halawani D, Tessier S, Anzellotti D, Bennett DA, Latterich M, LeBlanc AC. Caspase-mediated cleavage of actin and tubulin is a common feature and sensitive marker of axonal degeneration in neural development and injury. Sokolowski JD, Gamage KK, Heffron DS, LeBlanc AC, Deppmann CD, Mandell JW. Targets of caspase-6 activity in human neurons and Alzheimer disease. Klaiman G, Petzke TL, Hammond J, LeBlanc AC. Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. Horowitz PM, Patterson KR, Guillozet-Bongaarts AL, Reynolds MR, Carroll CA, Weintraub ST, et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, et al. Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice. Zhou L, Flores J, Noël A, Beauchet O, Sjostrom PJ, LeBlanc AC. Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment. LeBlanc AC, Ramcharitar J, Afonso V, Hamel E, Bennett DA, Pakavathkumar P, et al. Caspase-6 activity predicts lower episodic memory ability in aged individuals. Ramcharitar J, Afonso VM, Albrecht S, Bennett DA, LeBlanc AC. Activation of caspase-6 in aging and mild cognitive impairment. 2004 165:523–31.Īlbrecht S, Bourdeau M, Bennett D, Mufson EJ, Bhattacharjee M, LeBlanc AC. Active Caspase-6 and Caspase-6 cleaved Tau in neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer’s Disease. Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc AC.
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Caspase-6 activation in familial Alzheimer disease brains carrying amyloid precursor protein or presenilin I or presenilin II mutations. 2015 22:1676–86.Īlbrecht S, Bogdanovic N, Ghetti B, Winblad B, LeBlanc AC. Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Kaushal V, Dye R, Pakavathkumar P, Foveau B, Flores J, Hyman B, et al. Caspase-1 activation of caspase-6 in human apoptotic neurons. Guo H, Petrin D, Zhang Y, Bergeron C, Goodyer CG, LeBlanc AC. Multifactorial hypothesis and multi-targets for Alzheimer’s disease. Alzheimer’s disease drug development pipeline: 2020. These results indicate that Nlrp1, Casp1, and Casp6 represent rational therapeutic targets against cognitive impairment and inflammation in AD.Ĭummings J, Lee G, Ritter A, Sabbagh M, Zhong K. We conclude that Nlrp1, Casp1, or Casp6 are implicated in AD-related cognitive impairment, inflammation, and amyloidogenesis. IFN-γ was increased and total amyloid β peptide was decreased in genetically ablated Nlrp1, Casp1 or Casp6 J20 hippocampi. CXCL1 was also normalized by Casp6 genetic ablation. Increased pro-inflammatory cytokines, TNF-α and CXCL1, in the J20 hippocampus were normalized by Nlrp1 or Casp1 genetic ablation. Increased Iba1 +-microglia in the hippocampus and cortex of J20 brains were normalized by Casp1 and Casp6 ablation and reduced by Nlrp1 ablation. Reduced J20 hippocampal dentate gyrus and CA3 synaptophysin levels were normalized in genetically ablated J20. Hippocampal CA1 dendritic spine density of the mushroom subtype was reduced in J20, and normalized in genetically ablated J20 mice. Spatial learning deficits, assessed with the Barnes Maze, were normalized in genetically ablated J20, whereas memory recall was normalized in J20/Casp1 −/− and J20/Casp6 −/−, and improved in J20/ Nlrp1 −/− mice. Episodic memory deficits assessed with novel object recognition were normalized by genetic ablation of Nlrp1, Casp1, or Casp6 in J20 mice. To validate the Nlrp1-Casp1-Casp6 pathway in vivo, the APP Swedish/Indiana J20 AD transgenic mouse model was generated on either a Nlrp1, Casp1 or Casp6 null genetic background and mice were studied at 4–5 months of age. The sequential activation of Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing protein 1 (Nlrp1) inflammasome, Caspase-1 (Casp1), and Caspase-6 (Casp6) is implicated in primary human neuron cultures and Alzheimer Disease (AD) neurodegeneration.