Lysosomal dysfunction: Role in brain aging and Alzheimer's disease

Experiments were conducted to determine if treatment of slice cultures of rat frontal cortex with an inhibitor of two lysosomal enzymes resulted in pathological features seen in the aged human brain. Slices showed a large increase in the number of lysosomes in the somata and dendrites of pyramidal and non-pyramidal neurons after six days of treatment. Pyramidal neurons in layer III tended to collect greater numbers of lysosomes in the basal portion of the soma compared with those in layer V. Slices maintained for an additional four days without the inhibitor contained layer III pyramidal neurons that (i) had almost completely cleared their cell bodies and dendrites of lysosomes, and (ii) exhibited meganeurites between the soma and axon initial segment that appeared very similar to those found in the aged human cortex.; Cultured mouse hippocampal slices were also utilized to test hypotheses that endosomal-lysosomal dysfunction contributes to brain aging and Alzheimer's disease, specifically the formation of neurofibrillary tangles. Experimentally induced lysosomal dysfunction coupled with a confirmed risk factor for Alzheimer's disease, apolipoprotein E, led to a number of characteristic features of the aged human brain. Included among these were (i) robust increases in the concentrations of the lysosomal hydrolase cathepsin D, (ii) increased concentrations of phosphorylated fragments of the microtubule crosslinking protein tau, and (iii) early-stage neurofibrillary tangles. The types and distribution of intraneuronal neurofibrillary tangles found in cultured slices were not unlike the diversity found in hippocampus during early-stage human Alzheimer's disease. They were numerous in the subiculum and stratum oriens of hippocampal field CA1 and rarely found in the dentate gyrus and field CA3. Immunopositive neurons within cultured mouse hippocampal slices could also be organized into progressive stages proposed for neurofibrillary tangle development in human Alzheimer's disease. Electron microscopic analyses confirmed the changes observed with paired helical filament antibodies as neuronal cell bodies and their processes were often filled with long twisted bundles of neurofilaments. These results support the hypothesis that lysosomal dysfunction is linked to aspects of brain aging and Alzheimer's disease and provide a model for blocking age-related pathologies.