Editors' ChoiceAlzheimer’s Disease

Caspase-2: Divide and conquer

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Science Translational Medicine  02 Nov 2016:
Vol. 8, Issue 363, pp. 363ec176
DOI: 10.1126/scitranslmed.aaj2091

Tau is converted into insoluble, hyperphosphorylated inclusions in a group of neurodegenerative diseases—including Alzheimer’s disease (AD)—collectively called tauopathies. Memory impairment and neuronal death in animal models of these diseases can be uncoupled from the formation of these insoluble tau inclusions, suggesting that other forms of tau may drive neuronal network dysfunction and cognitive impairment. Now, Zhao and colleagues report that a product resulting from caspase-2 cleavage of tau resists fibrillation, promotes synaptic dysfunction, and results in neurodegeneration in mice. Importantly, decreasing caspase-2 beneficially impacted long-term memory in a mouse model of AD.

The investigators showed that caspase-2 cleavage of tau at Asp314 resulted in a truncation product, ∆tau314, which was present at higher levels in the brains of AD mice compared with wild-type control animals. Interestingly, ∆tau314 exhibited a reduced tendency to aggregate in sedimentation and thioflavin T incorporation assays but did promote the incorrect sorting of mutant tauP301L into the dendritic spines of cultured neurons, a key pathological process that precedes neuronal degeneration. Transgenic mice expressing tauP301L exhibited spatial memory deficits that were measured in the Morris water maze test. The memory impairments in these mice could be reversed by infusion of anti–caspase-2 morpholino oligonucleotides into the lateral ventricles of the mouse brain for 28 days. The improvements in memory function corresponded to a reduction in ∆tau314, linking the tau caspase-2 cleavage product to neurodegenerative behavioral deficits in vivo.

Growing evidence has implicated aberrant caspase activity in the neurodegeneration associated with AD and Huntington’s disease, as well as other unrelated pathologies. This has spurred substantial efforts to develop caspase inhibitors for clinical use, yet safety issues such as tumor growth during or after treatment are a concern, and none have currently been approved. The evidence provided by Zhao et al. lends additional weight to the prospect of specifically targeting the activity of caspase-2 in AD, although the development of safe and effective caspase inhibitors that show promise in animal models remains a significant challenge.

X. Zhao et al., Caspase-2 cleavage of tau reversibly impairs memory. Nat. Med. 10.1038/nm.4199 (2016). [Abstract]

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