The Lysosomal System in Neurons

Abstract

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.

Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration.

“…Enzyme activity was maintained in the absence of 80-kDa ,uCANP and remained proportional to the amount of 76-kDa isoform (Fig. 1C), confirming that the 76-kDa isoform is enzymatically active (20,37). Human brain ,uCANP was unstable in cell-free extracts; however, conversion of the 80-kDa isoform of ,LCANP to the smaller isoforms could be demonstrated in 1-mm slices of postmortem humar.…”

“…These actions regulate the assembly state and other dynamics of the proteins (15,54) and may underlie the suspected involvement of CANPs in membrane fusion (57,58) and trafficking (59). Abnormalities of the endosomal-lysosomal system are, in fact, an early marker of affected neurons in Alzheimer brain, and these abnormalities may alter APP processing (37,44). A further link between CANP activity and APP metabolism is suggested by the observation that phorbol esters, which activate a signal transduction cascade involving CANP and protein kinase C (12)(13)(14)(15), induce a phosphorylation-dependent increase in the secretion of APP derivatives in PC12 cells (19).…”

“…The degree of ,uCANP activation also did not significantly correlate with age within the age range studied. Because some neurons are degenerating in Alzheimer neocortex, we also examined the degree of ,uCANP activation in two brain areas where the neuronal dysfunction (37) has not advanced to evident neuronal degeneration (39). The ratio of 76-to 80-kDa ,uCANP isoforms was elevated in both putamen (46%; P < 0.005) and cerebellum (58%; P < 0.005) in the Alzheimer cases ( Fig.…”

“…In this regard, the degree of abnormal ,uCANP activation found in the Alzheimer neocortex inversely correlates (r = 0.87; P < 0.001) with levels of soluble APP in the brain (69). We speculate that decreased secretion of APP (60) and altered lysosomal/endosomal processing in Alzheimer brain (37,44) could both be partial consequences of ,uCANP activation. Finally, by altering the phosphorylation and proteolytic modification of cytoskeletal proteins, protracted low-level ,uCANP activation might contribute to neurofibrillary tangle formation and altered synaptic efficacy (61).…”

Hippocampal plasticity during the progression of Alzheimer’s disease

“…The underlying pathogenic mechanisms that trigger these structural synaptic alterations in the hippocampus during MCI and the onset of AD are unclear, yet several lines of evidence revealed that an aberrant expression of endosomal-lysosomal proteins occurs within hippocampal neurons even before the SP and NFT formation early in AD (Nixon et al, 1992; Cataldo et al, 1994, 1995; Nixon, 2005). Endosomal-lysosomal activity is an essential and dynamic organization of acidified cytoplasmic organelles which perform a variety of functions in neurons such as internalizing nutrients and neurotrophic factors, as well as degrading and recycling receptors (Nixon and Cataldo, 1995; Bishop, 2003).…”