Journal article Open Access
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 Ca2+ homeostasis, calpain activation, amyloid b 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.