Just as amyloid-β toxicity may be attenuated by proteases such as insulin degrading enzyme and neprilysin, tau toxicity may be circumvented by the highly conserved puromycin-sensitive aminopeptidase (PSA)—at least in fruit flies. Alzforum first reported this possibility following George Jackson’s presentation at last year’s Society for Neuroscience annual meeting. Work from the lab of Jackson’s UCLA colleague Dan Geschwind had identified PSA as being enriched in the cerebellum of tau mutant (P301L) mice. Because the cerebellum escapes the ravages of tau toxicity, Jackson and colleagues tested if PSA could rescue tau toxicity in a fly model of neurodegeneration. They found that low-level overexpression of the peptidase reduced tau and prevented neurodegeneration of the fly eye.
The findings are presented in depth in today’s Neuron. First author Stanislav Karsten and colleagues also present data pointing to an increase in PSA in postmortem frontal cortex samples taken from patients with frontotemporal dementia. This “may reflect its higher level of expression in neurons surviving after a long course of disease,” the authors write. They also note that PSA co-localizes around senile plaques in AD brain (see Minnasch et al., 2003), suggesting a link between amyloid deposition and tau pathology that is worth further investigation. See our original SfN meeting coverage for more details on this study.—Tom Fagan
- Minnasch P, Yamamoto Y, Ohkubo I, Nishi K. Demonstration of puromycin-sensitive alanyl aminopeptidase in Alzheimer disease brain. Leg Med (Tokyo). 2003 Mar;5 Suppl 1:S285-7. PubMed.
- Karsten SL, Sang TK, Gehman LT, Chatterjee S, Liu J, Lawless GM, Sengupta S, Berry RW, Pomakian J, Oh HS, Schulz C, Hui KS, Wiedau-Pazos M, Vinters HV, Binder LI, Geschwind DH, Jackson GR. A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration. Neuron. 2006 Sep 7;51(5):549-60. PubMed.