Autophagy is an important process, a form of cellular housekeeping in which broken proteins, damaged cell components, and other metabolic waste are tagged, packaged, and conveyed a lysosome for recycling. Lysosomes are membranes filled with enzymes and other molecular tools capable of breaking down most of what a cell will encounter in its lifetime. Most is not all, however, and over the course of a human life span lysosomes in the long-lived cells of the nervous system become weighed down with compounds they cannot effectively recycle. These lysosomes become bloated and dysfunctional, and their cells suffer due to rising levels of waste and breakage. This is, of course, a very high level and general description of a downward spiral. At the detailed level there is a great deal yet to be determined about exactly how this failure progresses.
Nerve cells, or neurons, are structurally quite different from most other cell types. They extend very long connections between one another, axons, which also need the service of lysosomes, just as much as the rest of the cell body. In the research noted below, the authors identify the failure of lysosomes to move along axons as a possible factor in the decline of autophagy in old nervous system tissue. It isn’t clear how this relates to the buildup of waste in lysosomes, and in fact one might take this as only a very preliminary examination of the issue of axonal transport of lysosomes. The researchers have identified a regulator they can use to artificially degrade this transport, but that isn’t the same as showing that changes in the regulator are relevant in normal aging: all it shows is that making autophagy worse – by any means – accelerates the age-related neurodegeneration that gives rise to conditions like Alzheimer’s disease. We already know this to be the case, and we already know that autophagy declines in effectiveness with age. A reason for continued investigation in this case is that the specific characteristics of lysosomal failure in axons produced in this study look very similar to those occurring in Alzheimer’s disease, but we should reserve judgement until further progress has been made.
The SENS rejuvenation research approach to lysosomal decline is to find ways to break down the specific molecular waste that the lysosome struggles with. The presence of this waste is a form of damage, a cause of aging, and it should be removed if aging is to be addressed. The philosophy here is that it is probably more cost-effective to make this potential repair and see what happens as a result than to take the time to first completely untangle the complexities of cellular biochemistry. Potential therapies that should improve the state of the system are in fact one of the best tools to aid in creating understanding, as success in repair establishes knowledge of causes and consequences that would be far harder to obtain through inspection only. Ichor Therapeutics is doing this for one form of waste that occurs in retinal cells, building the Lysoclear therapy for macular degeneration. In the context of the paper below, it would be most interesting to find out how the Ichor approach changes the behavior of lysosomes in retinal axons.
Researchers have discovered that defects in the transport of lysosomes within neurons promote the buildup of protein aggregates in the brains of mice with Alzheimer’s disease. The study suggests that developing ways to restore lysosome transport could represent a new therapeutic approach to treating the neurodegenerative disorder. A characteristic feature of Alzheimer’s disease is the formation of amyloid plaques inside the brain. The plaques consist of extracellular aggregates of a toxic protein fragment called β-amyloid surrounded by numerous swollen axons, the parts of neurons that conduct electric impulses to other nerve cells.
These axonal swellings are packed with lysosomes, cellular garbage disposal units that degrade old or damaged components of the cell. In neurons, lysosomes are thought to “mature” as they are transported from the ends of axons to the neuronal cell body, gradually acquiring the ability to degrade their cargo. The lysosomes that get stuck and accumulate inside the axonal swellings associated with amyloid plaques fail to properly mature, but how these lysosomes contribute to the development of Alzheimer’s disease is unclear. One possibility is that they promote the buildup of β-amyloid because some of the enzymes that generate β-amyloid by cleaving a protein called amyloid precursor protein (APP) accumulate in the swellings with the immature lysosomes.
Researchers investigated this possibility by impeding the transport of lysosomes in mouse neurons. The researchers found that neurons lacking a protein called JIP3 failed to transport lysosomes from axons to the cell body, leading to the accumulation of lysosomes in axonal swellings similar to those seen in Alzheimer’s disease patients. The swellings also accumulated APP and two enzymes – called BACE1 and presenilin 2 – that cleave it to generate β-amyloid. Neurons lacking JIP3 therefore generated increased amounts of β-amyloid. The researchers then removed one copy of the gene encoding JIP3 – halving the amount of JIP3 protein – from mice that were already prone to developing Alzheimer’s disease. These animals produced more β-amyloid and formed larger amyloid plaques, surrounded by an increased number of swollen axons. “Collectively, our results indicate that the axonal accumulations of lysosomes at amyloid plaques are not innocent bystanders but rather are important contributors to APP processing and amyloid plaque growth.”
Amyloid plaques, a defining feature of Alzheimer’s disease (AD) brain pathology, have long been recognized to contain an extracellular aggregate of the β-amyloid peptide that is surrounded by microglia and an abundance of swollen axons. These axons contain a massive accumulation of organelles that resemble lysosomes and/or hybrid organelles arising from the fusion of lysosomes with late endosomes and autophagosomes (subsequently referred to as lysosomes for simplicity). Despite their long-known and robust occurrence, the disease relevance of these lysosome-filled axonal swellings has not been established.
The high abundance of lysosomes within axonal swellings at amyloid plaques and their potential role as sites of APP processing raise questions concerning the fundamental mechanisms that govern axonal lysosome abundance. Multiple studies have identified late endosomes and autophagosomes within distal regions of axons that likely play key housekeeping functions by sequestering old or damaged proteins and organelles. However, to degrade and recycle their contents, these organelles must acquire lysosomal properties such as hydrolytic enzymes and a highly acidic lumen. To this end, these organelles are thought to undergo a maturation process within axons that is coupled with their retrograde axonal transport toward the neuronal cell body.
To test the contribution of axonal lysosomes to amyloid plaque pathology, we first sought to develop a genetic strategy to perturb axonal lysosome abundance. To this end, we identified an important role for mouse JNK-interacting protein 3 (JIP3) in regulating the abundance and maturation state of axonal lysosomes. Of particular interest, immature lysosomes accumulated in the axons of JIP3 knockout (KO) neurons in a manner that recapitulated the key molecular and morphological properties of plaque-proximal axonal lysosomes in AD, including the buildup of APP-processing machinery. Such changes in the abundance and/or localization of APP-processing proteins were accompanied by increased β-amyloid peptide production. We then tested the in vivo effect of depleting JIP3 in a mouse model of AD and found a dramatic worsening in the severity of amyloid plaque pathology. These observations support a model wherein the accumulation of lysosomes within local axonal swellings at plaques actively contributes to APP processing and plaque development and suggest that restoration of normal axonal lysosome transport and maturation could help to suppress the development and progression of AD brain pathology.