Alzheimer’s disease is characterized by the formation of beta-amyloid plaques, which are clumps of protein pieces in the tissue between nerve cells and neurofibrillary tangles, which are twisted tau protein filaments. The beta-amyloid plaques are thought to have toxic effects on the surrounding brain cells, although the exact role the plaques play in the progression of the disease is not well understood, such as whether they cause or are simply a byproduct of Alzheimer’s disease. It is also unclear what causes the process of plaque formation to begin, but it is thought that the process begins years before the symptoms of Alzheimer’s disease develop.
The amyloid cascade hypothesis postulates that the build-up of beta-amyloid plaques is a key first step in Alzheimer’s disease pathology, and that has been a major focus of research for more than 20 years. Several drugs have been developed that aimed to reduce amyloid-β production or aggregation; however, the drugs have failed in Phase III clinical trials. Now a new study conducted at NYU Grossman School of Medicine and the Nathan Kline Institute using mouse models of Alzheimer’s disease suggests the plaques form as a result of the failure of a process in the brain for getting rid of waste, and it is the breakdown of that waste removal process that ultimately results in neurodegeneration. That process begins well before the plaques start to form outside cells.
Metabolic waste products are recycled or removed by lysosomes, which are sacs of enzymes found in all cells. They are involved in the breakdown, recycling, and removal of waste from cells to maintain cellular homeostasis. That includes breaking down, removing, and recycling metabolic waste from normal cell processes and from disease, and breaking down cell components when they die. The latter is termed autophagy. Autophagy can be induced by cell stress or disease to remove abnormal proteins, damaged cell structures, and aggregates. The researchers explained that autophagy is markedly impaired in Alzheimer’s disease patients.
The new study saw the researchers track decreasing acid activity inside intact mouse cell lysosomes as cells became injured from Alzheimer’s disease. They developed imaging tests to track the removal of cellular waste and found that certain brain cell lysosomes became enlarged when they fused with autophagic vacuoles (AVs) filled with waste that had not been broken down, and that the AVs contained earlier forms of amyloid beta.
The researchers report that in neurons that are the most heavily damaged and will die, the vacuoles formed flower-like patterns and bulged out from the cells’ outer membranes, massing around the cell nucleus. “In more compromised yet still intact neurons, profuse Aß-positive AVs pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains.”
In different mouse models, the researchers found accumulations of amyloid beta formed filaments inside the cell, which is characteristic of Alzheimer’s disease, and almost fully formed plaques formed inside some of the damaged neurons. This is the first time that it has been demonstrated that rather than the damage associated with Alzheimer’s disease being caused by beta-amyloid build-up outside of brain cells, it is problems inside the lysosomes of brain cells where beta-amyloid first appears.
“β-amyloid plaque formation in AD has commonly been considered to originate from extracellular deposition of β-amyloid derived from secreted Aβ, which then triggers secondary neuritic dystrophy and neuronal cell death,” explained the researchers. “By contrast, our evidence in diverse AD models supports the opposite sequence—namely, extracellular plaques mainly evolve from intraneuronal build-up of β-amyloid within membrane tubules, forming a centralized amyloid ‘core’ within single intact PANTHOS neurons that subsequently degenerate to give rise to the classical senile plaque.” The researchers suggest that PANTHOS neurons are the origin of the vast majority of senile plaques in AD mouse models.”
The researchers say their findings could answer the question of why drugs that aim to reduce amyloid-β production or aggregation fail, and suggest it could be because brain cells are already crippled before the plaques fully form outside cells. The research could open up a new avenue for Alzheimer’s disease therapeutics that aim to reverse lysosomal dysfunction and rebalance acid levels inside the brain’s neurons.
You can read more about the study in the paper – Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques – which was recently published in Nature Neuroscience. DOI: s41593-022-01084-8.
The researchers are now working on developing experimental therapies that tackle the lysosomal problems they identified in their research and have shown that the gene PSEN1, which has long been known to cause Alzheimer’s disease, plays a role in lysosomal dysfunction. They have also shown that the neuronal damage in PSEN1 mouse models of Alzheimer’s disease can be reversed if proper acid levels in lysosomes are restored.