Does proteasome inhibition play a role in mediating neuropathology and neuron death in Alzheimer's disease?

An increasing number of studies have demonstrated evidence that inhibition of proteasome activity may play a causal role in mediating the neuropathology and neuron death observed in Alzheimer's disease (AD). These reports have clearly demonstrated that proteasome inhibition occurs in the AD brain, with numerous in vitro and in vivo studies elucidating the ability of proteasome inhibitors to induce AD-like neuropathology and even neuron death. In spite of these clear and significant findings, several important questions regarding the role of proteasome inhibition in AD remain unanswered. We propose that chronic low-level proteasome inhibition, but not severe and acutely toxic levels of proteasome inhibition, likely plays a role in mediating specific aspects of AD neuropathology. Experimental evidence supporting this hypothesis, as well as the scientific implications of this hypothesis are discussed.