This very interesting paper uses state-of-the-art techniques to assess properties of unique brain cells in a mouse model of AD as well as in human samples. Cell lines are also included. However, it is premature to dispute “the widely held belief that proteasome inhibition is a prominent feature of Alzheimer’s disease pathology (Fergusson et al., 1996)”. The methods to assess proteasome activity used by Orre et al. in this paper do not distinguish between the different fully assembled forms of the proteasome, because they only assess peptidase activities and individual subunit levels. It is possible that the activities of the 20S proteasome and/or immuno-proteasome are increased, while 26S proteasome activity decreases. It is also possible that the levels of individual subunits change without affecting fully assembled proteasome levels. The methods used to assess proteasome activity do not assess these possibilities. In-gel assays and glycerol gradient fractionation, for example, are more valid tests to assess the full nature of proteasome activity. They take into consideration...  Read more

This very interesting paper uses state-of-the-art techniques to assess properties of unique brain cells in a mouse model of AD as well as in human samples. Cell lines are also included. However, it is premature to dispute “the widely held belief that proteasome inhibition is a prominent feature of Alzheimer’s disease pathology (Fergusson et al., 1996)”. The methods to assess proteasome activity used by Orre et al. in this paper do not distinguish between the different fully assembled forms of the proteasome, because they only assess peptidase activities and individual subunit levels. It is possible that the activities of the 20S proteasome and/or immuno-proteasome are increased, while 26S proteasome activity decreases. It is also possible that the levels of individual subunits change without affecting fully assembled proteasome levels. The methods used to assess proteasome activity do not assess these possibilities. In-gel assays and glycerol gradient fractionation, for example, are more valid tests to assess the full nature of proteasome activity. They take into consideration the quaternary structure that is essential for proteasome activity and high dependency on ATP for the 26S proteasome, the one that degrades ubiquitinated proteins.

References:
Fergusson J, Landon M, Lowe J, Dawson SP, Layfield R, Hanger DP, Mayer RJ. Pathological lesions of Alzheimer's disease and dementia with Lewy bodies brains exhibit immunoreactivity to an ATPase that is a regulatory subunit of the 26S proteasome. Neurosci Lett. 1996 Nov 29;219(3):167-70. Abstract

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