Autophagy mediates the degradation of intracellular macromolecules and organelles within lysosomes. There are three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Heat shock protein 70.1 (Hsp70.1) exhibits dual functions as a chaperone protein and a lysosomal membrane stabilizer. Since chaperone-mediated autophagy participates in the recycling of ∼30% cytosolic proteins, its disorder causes cell susceptibility to stress conditions. Cargo proteins destined for degradation such as amyloid precursor protein and tau protein are trafficked by Hsp70.1 from the cytosol into lysosomes. Hsp70.1 is composed of an N-terminal nucleotide-binding domain (NBD) and a C-terminal domain that binds to cargo proteins, termed the substrate-binding domain (SBD). The NBD and SBD are connected by the interdomain linker LL1, which modulates the allosteric structure of Hsp70.1 in response to ADP/ATP binding. After the passage of the Hsp70.1-cargo complex through the lysosomal limiting membrane, high-affinity binding of the positive-charged SBD with negative-charged bis(monoacylglycero)phosphate (BMP) at the internal vesicular membranes activates acid sphingomyelinase to generate ceramide for stabilizing lysosomal membranes. As the integrity of the lysosomal limiting membrane is critical to ensure cargo protein degradation within the acidic lumen, the disintegration of the lysosomal limiting membrane is lethal to cells. After the intake of high-fat diets, however, β-oxidation of fatty acids in the mitochondria generates reactive oxygen species, which enhance the oxidation of membrane linoleic acids to produce 4-hydroxy-2-nonenal (4-HNE). In addition, 4-HNE is produced during the heating of linoleic acid-rich vegetable oils and incorporated into the body via deep-fried foods. This endogenous and exogenous 4-HNE synergically causes an increase in its serum and organ levels to induce carbonylation of Hsp70.1 at Arg469, which facilitates its conformational change and access of activated μ-calpain to LL1. Therefore, the cleavage of Hsp70.1 occurs prior to its influx into the lysosomal lumen, which leads to lysosomal membrane permeabilization/rupture. The resultant leakage of cathepsins is responsible for lysosomal cell death, which would be one of the causative factors of lifestyle-related diseases.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that reduces cell injuries via detoxification of lipid-peroxidation product, 4-hydroxy-2-nonenal (hydroxynonenal). It is generated exogenously via deep-frying of linoleic acid-rich cooking oils and/or endogenously via oxidation of fatty acids involved in biomembranes. Although its toxicity for human health is widely accepted, the underlying mechanism long remained unknown. In 1998, Yamashima et al. have formulated the \"calpain-cathepsin hypothesis\" as a molecular mechanism of ischemic neuronal death. Subsequently, they found that calpain cleaves Hsp70.1 which became vulnerable after the hydroxynonenal-induced carbonylation at the key site Arg469. Since it is the pivotal aberration that induces lysosomal membrane rupture, they suggested that neuronal death in Alzheimer\'s disease similarly occurs by chronic ischemia via the calpain-cathepsin cascade triggered by hydroxynonenal. For nearly three decades, amyloid β (Aβ) peptide was thought to be a root substance of Alzheimer\'s disease. However, because of both the insignificant correlations between Aβ depositions and occurrence of neuronal death or dementia, and the negative results of anti-Aβ medicines tested so far in the patients with Alzheimer\'s disease, the strength of the \"amyloid cascade hypothesis\" has been weakened. Recent works have suggested that hydroxynonenal is a mediator of programmed cell death not only in the brain, but also in the liver, pancreas, heart, etc. Increment of hydroxynonenal was considered an early event in the development of Alzheimer\'s disease. This review aims at suggesting ways out of the tunnel, focusing on the implication of hydroxynonenal in this disease. Herein, the mechanism of Alzheimer neuronal death is discussed by focusing on Hsp70.1 with a dual function as chaperone protein and lysosomal stabilizer. We suggest that Aβ is not a culprit of Alzheimer\'s disease, but merely a byproduct of autophagy/lysosomal failure resulting from hydroxynonenal-induced Hsp70.1 disorder. Enhancing ALDH2 activity to detoxify hydroxynonenal emerges as a promising strategy for preventing and treating Alzheimer\'s disease.