New research suggests another possible mechanism for Alzheimer’s

By Dr. Liji Thomas, MDAug 13 2019

Neurofibrillary plaques and tau protein are among the most widely known pathological entities characterizing Alzheimer’s disease (AD), but new research at the University of California, Riverside, has come up with another plausible explanation for this debilitating disorder.

AD affects 5.5 million adults in the US, with progressive impairment of memory, thinking and decision making. This ultimately ends in their requiring permanent and increasing care until the end of their lives. The reason for this affliction has been thought to lie in the aggregation of strange deposits composed of beta-amyloid protein which lies in clumps between brain cells. Another protein called tau forms twisted tangles that accumulate inside the cells.

Tyler Lambeth (left) and Ryan Julian in the lab. Image Credit: Julian lab, UC Riverside

So far, says researcher Ryan R. Julian, “The dominant theory based on beta-amyloid buildup has been around for decades, and dozens of clinical trials based on that theory have been attempted, but all have failed.” He suggests that the reason why all therapies built around these proteins fail to succeed is that they do not address the fundamental cause of the disease, which is the prior failure of lysosomal function. This would mean that AD is a lysosomal storage disorder.

Every cell must maintain a balance between protein synthesis and breakdown. Non-functional proteins must be recycled, using one or more of several pathways like proteasomes and autophagy of several sorts. Autophagy is a process involving lysosomes. Lysosomes are organelles that handle old and worn out parts within the cell. Here non-functional protein is broken down into the constituent molecules by powerful and varied digestive enzymes like cathepsins, to be then transported outwards to the cell cytoplasm. There they are recycled to form necessary cell structures as required.

Lysosomes particularly target long-lived proteins that have outlived their function, typically because of unwanted chemical modifications. The amino acids that compose the protein’s primary structure undergo spontaneous changes like isomerization and epimerization over time. Here the position of various groups within the carbon chain is switched without any overall change in the chemical composition.

These rapid and common spontaneous modifications in long-lived proteins have significant but almost undetectable effects on the protein structure, converting it to its mirror image. This is detectable by the change in the direction of polarized light beamed through them. Aspartic acid is the amino acid most affected by isomerization, while epimerization often affects the amino acid asparagine. Earlier experiments have shown that isomerization of aspartic acid is lethal to mice within weeks, and an enzyme is already present in the body to reverse this modification, indicating its importance.

Enzymes are typically specifically designed to latch on to equally specific parts of the protein to be acted upon. For instance, just as a left-handed glove doesn’t fit the right hand, these proteins don’t fit the body’s enzymes. Thus, when an amino acid like aspartic acid isomerizes into 1-isoAsp, no enzyme can break down that peptide fragment, resulting in failure of digestion even by the most powerful lysosomal enzyme, cathepsin 1. This results in unduly long peptide fragments persisting undigested within the lysosome. Such non-functional lysosomes build up at the periphery of the cell, slowly causing the death of the cell. The effects are most marked in nerve cells, which are already mature. The result is a lysosomal storage disorder.

Lysosomal storage disorders typically occur in early life because of a genetic error. Thus patients with these diseases manifest the symptoms and signs within weeks of birth, and often die within one or two years. This is where AD differs from other lysosomal storage diseases. It shows the same type of lysosomal storage, but at a much later period of life, and progressing much more slowly in many cases.

The reasons for the non-function of the lysosomes in AD may be spontaneous modifications of the chemical structure of the long-lived beta-amyloid and tau proteins. Julian’s team set out to show that such changes make these proteins resistant to enzymatic degradation within the lysosomes.

They did this by exposing synthetic peptides to a full series of lysosomal enzymes. They found that the isomerization and epimerization led to almost complete shut-down of digestion of peptide sequences surrounding these modified amino acids. The presence of these almost undetectable changes in proteins like tau and beta-amyloid result in their resistance to enzymatic degradation, and as a consequence they build up in the brain cell.

Julian explains, “Long-lived proteins become more problematic as we age and could account for the lysosomal storage seen in Alzheimer's, an age-related disease.”

The researchers also found that isomerization of aspartic acid at positions 1 and 7 of the carbon chain occurred very rapidly, even before the formation of plaques. The reason for lysosomal failure is therefore the spontaneous chemical modification of the enzyme substrates, and this precipitates the chain of events ending in AD, namely, disturbances of protein breakdown, formation of plaques, and abnormal tau protein.

The subtle nature of the change explains why it has not been picked up so far despite the intense research on AD. These alterations increase in number as the protein’s lifespan increases. This could explain why AD occurs with increasing age.

This innovative study throws up the possibility of evolving effective therapies to clear out or recycle long-lived or modified proteins via autophagy. One important avenue of new research would be to find drugs that can upregulate the process of autophagy within the neurons to prevent AD.

Being able to prevent spontaneous modifications of this sort would be also useful in other diseases of the elderly such as age-related macular degeneration (AMD) and other neurodegenerative illnesses.

Julian said. “If we are correct, it would open up new avenues for treatment and prevention of this disease.”