title: Reconsider Alzheimer's disease by the 'calpain-cathepsin hypothesis'--a perspective review.
abstract: Alzheimer's disease (AD) is characterized by slowly progressive neuronal death, but its molecular cascade remains elusive for over 100 years. Since accumulation of autophagic vacuoles (also called granulo-vacuolar degenerations) represents one of the pathologic hallmarks of degenerating neurons in AD, a causative connection between autophagy failure and neuronal death should be present. The aim of this perspective review is at considering such underlying mechanism of AD that age-dependent oxidative stresses may affect the autophagic-lysosomal system via carbonylation and cleavage of heat-shock protein 70.1 (Hsp70.1). AD brains exhibit gradual but continual ischemic insults that cause perturbed Ca(2+) homeostasis, calpain activation, amyloid β deposition, and oxidative stresses. Membrane lipids such as linoleic and arachidonic acids are vulnerable to the cumulative oxidative stresses, generating a toxic peroxidation product 'hydroxynonenal' that can carbonylate Hsp70.1. Recent data advocate for dual roles of Hsp70.1 as a molecular chaperone for damaged proteins and a guardian of lysosomal integrity. Accordingly, impairments of lysosomal autophagy and stabilization may be driven by the calpain-mediated cleavage of carbonylated Hsp70.1, and this causes lysosomal permeabilization and/or rupture with the resultant release of the cell degradation enzyme, cathepsins (calpain-cathepsin hypothesis). Here, the author discusses three topics; (1) how age-related decrease in lysosomal and autophagic activities has a causal connection to programmed neuronal necrosis in sporadic AD, (2) how genetic factors such as apolipoprotein E and presenilin 1 can facilitate lysosomal destabilization in the sequential molecular events, and (3) whether a single cascade can simultaneously account for implications of all players previously reported. In conclusion, Alzheimer neuronal death conceivably occurs by the similar 'calpain-hydroxynonenal-Hsp70.1-cathepsin cascade' with ischemic neuronal death. Blockade of calpain and/or extra-lysosomal cathepsins as well as scavenging of hydroxynonenal would become effective AD therapeutic approaches.
authors.affiliation: Department of Restorative Neurosurgery, Kanazawa University Graduate School of Medical Science, Takara-machi 13-1, Kanazawa 920-8641, Japan. yamashima215@gmail.com
authors.forename: Tetsumori
authors.initials: T
authors.lastname: Yamashima
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002154:Calpain / Q000378:metabolism*; D002403:Cathepsins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; C081884:heat-shock protein 70.1; D002403:Cathepsins; D002154:Calpain