Abstract:

Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disorder characterized by loss in memory, cognition, and executive function and activities of daily living. AD pathogenesis has been shown to involve loss of neurons and synapses, cholinergic deficits, amyloid-beta protein (Aβ) deposition, tau protein hyperphosphorylation, and neuroinflammation. Among the various cell pathologic events observed in AD, changes in Aβ metabolism proceed fastest, often preceding clinical symptoms. Since the detection of immunoreactive and enzymatically active cathepsin B (cathB; EC 3.4.22.1) in association with amyloid deposits there has been ongoing interest in possible functions of this lysosomal cysteine protease in AD, and intense research has been done during the past decades to learn more about the possible place of the enzyme in disease pathophysiology. Soon it became clear that cathB is not a bystander but an active player, which is prominently and in many ways involved in AD pathology. However, findings from different groups are controversial and confusing. We herein try to draw attention to the Janus-faced nature of cathB in AD, in that the enzyme may contribute to both neuroprotection and neurodegeneration. Although we have to acknowledge that human morally (good, bad) and aesthetic (ugly) categories are not really suitable to describe cell pathologic processes, we will use these terms to clearly separate studies showing “positive” (in the sense of lowering AD pathology) from those demonstrating “negative” (increasing AD pathology) properties of cathB in AD.