10.1016/j.pneurobio.2013.02.004
https://zenodo.org/records/895448
oai:zenodo.org:895448
Yamashima, Tetsumori
Tetsumori
Yamashima
Reconsider Alzheimer's disease by the 'calpain–cathepsin hypothesis'—A perspective review
Zenodo
2013
2013-06-01
Other (Open)
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.