Decreased lysosomal acidity identified as overlooked ‘culprit’ in Alzheimer’s disease

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Decreased lysosomal acidity identified as overlooked ‘culprit’ in Alzheimer’s disease

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Decreased lysosomal acidity identified as overlooked ‘culprit’ in Alzheimer’s disease

Many studies of Alzheimer’s disease have cited the buildup of plaque in the brain as the main cause, but the case is far from over, especially according to a team at New York University.

In newly published research, scientists detail how a drop in acidity in cellular cleaning organelles called lysosomes serves as earlier evidence of the disease’s onset , and they have shown that restoring proper acidity levels can rescue neurons from irreversible damage.

The accumulation of beta-amyloid in the brain contributes to the neurodegeneration of Alzheimer’s disease, a concept that has been around for decades and has guided much of the research into potential treatments.

In recent years, however, some promising drugs developed against these plaques have failed.

While the amyloid hypothesis remains a very active branch of Alzheimer’s research, some are looking elsewhere for answers, and those studying lysosomal function are discovering some very valuable insights.

Lysosomes are organelles found in the cells of many animals that house acid enzymes that break down, remove and recycle waste.

For this reason, they are known as the cell’s garbage disposal system, and recent studies have begun to show how dysfunction of this system plays a role in the neuronal damage seen in Alzheimer’s disease.

An interesting 2019 study showed that amyloids are able to flip their molecular structure so that lysosomes cannot recognize them and clear them out.

The resulting buildup of failed lysosomes is thought to contribute to neuronal damage, and the study supports a 2015 Yale University study showing that it also enhances the buildup of toxic proteins.

The new study adds further weight to this line of thinking, and by demonstrating how lysosomal dysfunction can drive neuronal damage before amyloid plaques are fully formed.

The authors used mice bred to develop Alzheimer’s disease and tracked acid levels in lysosomes as cells were injured by the disease.

Imaging of lysosomes showed that as neurons were damaged, their acidity levels decreased.

Some of these lysosomes became larger as they interacted with vesicles filled with waste products that had not been broken down, causing the vesicles to cluster into flower-like bulges around the cell membrane.

Some of these vesicles were found to contain early forms of beta-amyloid, which went on to form filaments within cells and developed into fully formed plaques in some damaged neurons.

“Our results are the first to attribute the neuronal damage observed in Alzheimer’s disease to problems inside the lysosomes of brain cells, where beta-amyloid Proteins appear first.

Previously, working hypotheses have mostly attributed the damage seen in Alzheimer’s disease to what happens after amyloid builds up outside brain cells, rather than what happens before and from inside neurons.”

Scientists are now working to develop treatments for this form of lysosomal dysfunction. In previous work, they linked lysosomal dysfunction to a gene long linked to Alzheimer’s disease, PSEN1, and now they have been able to show how this form of neuronal damage works by restoring lysosomal acidity reversed to normal levels.

“This new evidence changes our fundamental understanding of how Alzheimer’s disease progresses; it also explains why many experimental therapies aimed at clearing amyloid plaques have failed to halt disease progression, as plaques develop in cells Brain cells are crippled before the outer shell is fully formed,” said study senior investigator Ralph A. Nixon. “Our study suggests that future treatments should focus on reversing lysosomal dysfunction and rebalancing acid levels within neurons of the brain.”

The study was published in the journal Nature Neuroscience .

Decreased lysosomal acidity identified as overlooked ‘culprit’ in Alzheimer’s disease

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