Author(s):
Currently, about 50 million people worldwide are suffering from Alzheimer’s disease, and most of the therapeutic drugs including novel antibodies against amyloid β or Tau proteins have failed in clinical trials. Amyloid β, neurofibrillary tangles, autolysosomes, multivesicular bodies, and multilamellar structures are seen in the patient brain as neuropathological hallmarks of Alzheimer’s disease. Especially, amyloid β accumulation had been considered its main cause, but the amyloid cascade hypothesis was proven to be incomplete and imprecise, if not wrong. Most of the nearly 200 transgenic mouse models of Alzheimer’s disease, although being characterized by extensive amyloid plaque pathology, don’t show substantial neuronal loss as seen in human Alzheimer brains. Furthermore, the PET analysis data showed that the amount of amyloid β deposited in the human brain does not correlate well with the degree of clinical symptoms. Since depositions of amyloid β are known to occur after the appearance of behavioral and synaptic abnormalities, and early lysosomal abnormalities have been implicated for the occurrence of neuronal death, there should be another oxidative stressor inducing the lysosomal disorder. Here, the author reports that the Japanese macaque monkey brains after the injections of lipid-peroxidation product ‘hydroxynonenal’ for 12 weeks, show very similar ultrastructural pathology with human Alzheimer brains. Although amyloid β deposition was not seen, multivesicular bodies with the potency of amyloid β accumulation were often observed in the vicinity of degenerating membranes of Golgi apparatus and rough ER. Intriguingly, hydroxynonenal-treated monkeys showed evidence of the lysosomal membrane permeabilization/rupture and the widespread neuronal degeneration/death. Since neuronal degeneration/death associated with formation of numerous autolysosomes and synaptic abnormalities were recapitulated without an implication of amyloid β, it is conceivable that the real culprit of Alzheimer’s disease is not amyloid β but hydroxynonenal. Here, the “calpain-cathepsin hypothesis” is highlighted to reconsider the molecular mechanism of Alzheimer’s disease.
