Alzheimer’s Disease - A New Hypothesis
Alzheimer’s disease is primarily an affliction of the elderly. Its incidence doubles for every half decade after age 65. Beginning with mild cognitive impairment, it is a dementia that inexorably progresses until it robs victims of memory, mobility, dignity, and, ultimately, their life.
What’s particularly frustrating for scientists who study the disease is that despite decades of intense research, its cause is unknown, exactly how it kills nerve cells is still a mystery, and the treatments devised to date that attempt to stem its march have largely proved ineffective.
Alzheimer’s isn’t the only form of dementia, but it accounts for about 70% of all cases worldwide. Broadly speaking, there are two forms of the disease. One, termed early onset, commonly strikes just after middle age, and before age 65. The other, called sporadic or late onset Alzheimer’s, occurs later in life. There is reasonable evidence that both forms of the disease have a genetic basis, although, except in some rare cases, not a simple Mendelian one.
At the cellular level, Alzheimer’s is characterized by some dramatic pathological structures found in the brains of its sufferers. These include the so-called “plaques” that occur outside of the cells in the brain, and “tangles” that appear intracellularly. The plaques are composed of aggregates of fragments of a protein called APP, or amyloid precursor protein. APP is a transmembrane protein that is critical for normal neuronal function. The fragments responsible for plaques are produced by two membrane bound proteolytic enzymes, 𝜷 and 𝛾 secretases that act on APP. The result of their proteolysis are protein pieces (peptides) of various lengths called A-𝜷. These bind tightly together to form the plaques characteristic of the disease. The tangles, on the other hand, are constructed from a protein called tau that plays a role in stabilization of microtubules, the molecular highways of cells. Tau needs to have phosphate groups added to it in order to function, but above normal phosphorylation (hyperphosphorylation) seems to cause tau to aggregate, thereby forming the tangles typical of the diseased neurons of Alzheimer’s victims.
For nearly twenty years and until very recently it was thought that the plaques found in Alzheimer’s sufferers brains were not only symptomatic of the disease but also causative – the “amyloid cascade hypothesis”. One quite compelling piece of evidence for it was that people with Down syndrome, who have an extra 21st chromosome, almost invariably show Alzheimer symptoms before the age of 40. It turns out that the gene for APP is found on the 21st chromosome, and the extra chromosome results in the production of an excess of APP. The thought was that having an abnormal increase in APP made it more likely to have excessive A-𝜷 peptide and therefore heightened plaque formation. Additional evidence comes from patients with early onset familial Alzheimer’s disease who have been found to bear mutations in the APP gene, or, alternatively, the genes that encode one of the two secretases. Again, these changes are thought to increase the likelihood of forming plaques and are added evidence for the amyloid cascade theory.
If the amyloid cascade hypothesis is correct, then it makes sense to devise agents that target the plaques or the enzymes that break the APP protein into the peptides that aggregate into them. In fact, several such drugs have been developed and tested in clinical trials. To date, all have failed to provide convincing evidence that they are effective, although some are still in the pipeline. The result of these disappointments has been that the amyloid hypothesis has come into disfavor.
There have been no shortage of alternative ideas. A recent paper (1) has provided evidence for a theory that acknowledges the role of amyloid in the etiology of Alzheimer’s but adds an additional twist.
First, some background. As I’ve noted in previous posts, we are literally not the same person we were minutes, hours, and days ago. In particular, our old proteins are continually being destroyed, their component amino acids recycled, and new proteins synthesized to take their place. The process of protein degradation is complex, but one critical pathway, called autophagy (“self eating”), utilizes small membrane-bound vesicles, lysosomes, and the host of digestive enzymes within them, to rid cells of old and aberrant proteins and other macromolecules.
Autophagy is an essential process necessary for maintaining homeostasis, but problems arise when a macromolecule can’t be digested. The result – the lysosome fills with undigested macromolecules. A cascade of secondary effects can subsequently occur, ultimately leading to cellular damage and cell death. Some 70 different so called lysosomal “storage” diseases are known, all caused by mutations that affect genes responsible for various functions of the organelle. Many mutations effect neurons because nerve cells aren’t replaced very often. And most of these diseases are fatal, often killing afflicted individuals early in life.
What has this to do with Alzheimer’s, a disease of the elderly? It turns out that amyloid aggregates are targets of lysosomes. But in Alzheimer’s they can’t be readily digested. But why might not? What’s preventing them from being broken down? The papers cited above place blame on the processes of isomerization and epimerization of the amino acid aspartic acid.
Here’s a simplified explanation of these two terms that doesn’t require diving deep into the muddy waters of organic chemistry. Aspartic acid is one of two amino acids (the monomers of proteins) that bears two acid groups. When one amino acid binds to another during the process of protein synthesis, an acid group of one joins with the amino group of another, forming a peptide bond. Aspartic acid is no exception. One of its two acid groups, a particular one, is involved in forming the peptide bond. But sometimes, especially in older proteins, the second acid group, the wrong one, inserts itself and substitutes for the normal one. This results in a subtle but significant change in the three dimensional structure of the protein. Epimerization produces a similar result, although it operates via a different process. In both cases the protein becomes increasingly resistant to breakdown in the lysosome.
The paper by Lambeth et al put together three observations to devise a new theory for the origin of Alzheimer’s disease. First, they point to the substantial evidence that aggregates of the A-𝜷 peptide undergo isomerization and epimerization. Second, they state that there is no doubt that A-𝜷 peptides are found in lysosomes. And finally, they note that the lysosomes in Alzheimer’s disease look like those found in lysosomal storage diseases. The Lambeth paper summarizes: “…Alzheimer’s disease would essentially represent a different type of lysosomal storage disorder… Rather than failure of a [defective] enzyme … to clear waste molecules, failure to digest or transport modified waste molecules would … eventually lead to lysosomal storage [disease].”
Buttressing Lambeth et al’s case is that there is increasing evidence (2) that another neurodegenerarative disease, Parkinson’s, is also a lysosomal disorder. Like Alzheimer’s disease, Parkinson’s is characterized by the appearance of pathological inclusions (Lewy bodies) in specific areas of the brain. In the case of Parkinson’s, a different protein, α-synuclein, is involved. Both diseases result in the death of sets of particular neurons.
If Alzheimer’s and Parkinson’s diseases (and perhaps other neurodegenerative diseases) are truly lysosome storage disorders, and if the disfunction of the lysosome precedes the appearance of plaques and Lewy body inclusions, it may change how scientists devise treatments. We’ll see. Over the years, there have been many different theories as what causes Alzheimer’s disease. We still don’t have definitive evidence that any one is correct. If Lambeth et al.’s conjecture is on target, it would be a major advance.
1. “Spontaneous isomerization of long-lived proteins provides a molecular mechanism for the lysosomal failure observed in Alzheimer’s Disease”, T. R. Lambeth et al., ACS Cent. Sci.5, 8, 1387-1395 (2019).
2. "Is Parkinson’s disease a lysosomal disorder?”, AD Klein and JR Mazzulli, Brain 141, 2255–2262 (2018).