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Cited by 2 publications
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Disturbed lysosomal function may be implicated at several stages of Alzheimer's pathogenesis. Lysosomes and acid hydrolases accumulate in the majority of neocortical pyramidal neurons before typical degenerative changes can be detected, indicating that altered lysosome function is among the earliest markers of metabolic dysfunction in Alzheimer's disease. These early alterations could reflect accelerated membrane and protein turnover, defective lysosome or hydrolase function, abnormal lysosomal trafficking or any combination of these possibilities. Because APP is partly metabolized in lysosomes, early disturbances in lysosomal function could promote the production of abnormal and/or neurotoxic APP fragments within intact cells. Lysosomal abnormalities progressively worsen as neurons begin to degenerate. Based on existing literature on cell death, increased perturbation and instability of the lysosomal system may be expected to contribute to the atrophy and eventual lysis of the neuron. Finally, the release of hydrolase-filled lysosomes and lipofuscin aggregates from dying neurons accounts for the abundant deposition of enzymatically active acid hydrolases of all classes in the extracellular space--a phenomenon that may be unique to Alzheimer's disease. Acting on APP present in surrounding dystrophic neurites, cellular debris and astrocyte processes, dysregulated hydrolases may cleave APP in atypical sequential patterns, thereby generating self-aggregating protease-resistant APP fragments that can be only processed to beta-amyloid. Genetic mutations or posttranslational factors of APP should further enhance the generation of amyloidogenic fragments by a dysregulated lysosomal system. Given that very little, if any, beta-amyloid is detected intracellularly, yet extracellular beta-amyloid is very abundant, our data suggest that the final steps of APP processing and the generation of most beta-amyloid in the brain parenchyma occur extracellularly and may involve one or more lysosomal proteases.
Disturbed lysosomal function may be implicated at several stages of Alzheimer's pathogenesis. Lysosomes and acid hydrolases accumulate in the majority of neocortical pyramidal neurons before typical degenerative changes can be detected, indicating that altered lysosome function is among the earliest markers of metabolic dysfunction in Alzheimer's disease. These early alterations could reflect accelerated membrane and protein turnover, defective lysosome or hydrolase function, abnormal lysosomal trafficking or any combination of these possibilities. Because APP is partly metabolized in lysosomes, early disturbances in lysosomal function could promote the production of abnormal and/or neurotoxic APP fragments within intact cells. Lysosomal abnormalities progressively worsen as neurons begin to degenerate. Based on existing literature on cell death, increased perturbation and instability of the lysosomal system may be expected to contribute to the atrophy and eventual lysis of the neuron. Finally, the release of hydrolase-filled lysosomes and lipofuscin aggregates from dying neurons accounts for the abundant deposition of enzymatically active acid hydrolases of all classes in the extracellular space--a phenomenon that may be unique to Alzheimer's disease. Acting on APP present in surrounding dystrophic neurites, cellular debris and astrocyte processes, dysregulated hydrolases may cleave APP in atypical sequential patterns, thereby generating self-aggregating protease-resistant APP fragments that can be only processed to beta-amyloid. Genetic mutations or posttranslational factors of APP should further enhance the generation of amyloidogenic fragments by a dysregulated lysosomal system. Given that very little, if any, beta-amyloid is detected intracellularly, yet extracellular beta-amyloid is very abundant, our data suggest that the final steps of APP processing and the generation of most beta-amyloid in the brain parenchyma occur extracellularly and may involve one or more lysosomal proteases.
The lysosomal system has often been considered a prominent morphologic marker of distressed or dying neurons. Lysosomes or their constituent hydrolases have been viewed in different neuropathologic states as either initiators and direct agents of cell death, agents of cellular repair and recompensation, effectors of end-stage cellular dissolution, or autolytic scavengers of cellular debris. Limited data and limitations of methodology often do not allow these potential roles to be discriminated. In all forms of neurodegeneration, it may be presumed that lysosomes ultimately rupture and release various hydrolases that promote cell autolysis during the final stages of cellular disintegration. Beyond this perhaps universal contribution to cell death, the degree to which the lysosomal system may be involved in neurodegenerative states varies considerably. In many conditions, morphologic evidence for activation of the lysosomal system is minimal or undetectable. In other cases, lysosomal activation is evident only when other morphologic signs of cell injury are also present. This level of participation may be viewed as either an attempt by the neuron to compensate for or repair the injury or a late-stage event leading to cell dissolution. The early involvement of the lysosomal system in neurodegeneration occurs most commonly in the form of intraneuronal accumulations of abnormal storage profiles or residual bodies (tertiary lysosomes). Very often the lysosomal involvement can be traced to a primary defect or dysfunction of lysosomal components or to accelerated or abnormal membrane breakdown that leads to the buildup of modified digestion-resistant substrates within lysosomes. Because they are often striking, changes in the lysosomal system are a sensitive morphologic indicator of certain types of metabolic distress; however, whether they reflect a salutary response of a compromised neuron or a mechanism to promote cell death and removal of debris from the brain remains to be established for most conditions. Factors that may influence the lysosomal response during lethal neuronal injury include species differences, stage of neuronal development, duration of injury and pace of cell death. The lysosomal system may be more closely coupled to certain forms of neuronal cell death in lower vertebrate or invertebrate systems than in mammalian systems.
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