Angélique Igel-Egalon, a research engineer with the Protein Macro-assembly and Prion Diseases-MAP2 team at INRA in Jouy-en-Josas, discusses recent studies suggesting that the propagation mechanism underlying Alzheimer’s disease, the most widespread neurodegenerative disease worldwide, is similar to the mechanism involved in prion diseases.
More than 50 forms of dementia resulting from neurodegenerative diseases have been identified to date, with Alzheimer’s being the most common. Today, an estimated 35 million individuals live with the disease worldwide, and that number could grow to 115 million in the next 30 years. In France, the NGO France-Alzheimer estimates that 25% of individuals over 65 will be diagnosed with Alzheimer’s disease by 2020.
Although Alzheimer’s can be the result of a genetic condition in some rare cases, the major risk factor remains aging. This means that, as life expectancy increases, so does the prevalence of this disease.
Yet recent studies also suggest that, under certain conditions, Alzheimer’s may be transmitted from one individual to another. The underlying mechanism exhibits similarities with prion diseases such as Creutzfeldt-Jakob disease, dozens of cases of which occurred during the “mad cow” crisis. Angélique Igel-Egalon tells us more.
Alzheimer’s disease, a condition related to proteins
Symptomatically, Alzheimer’s disease manifests itself through the drastic deterioration of mental and physical faculties caused by the death of brain neurons. When scientists analyze the brains of patients who have died of the disease, they identify two types of protein deposits.
Proteins are large molecules made up of a chain of smaller molecules, called amino acids. They are the building blocks of living things, as the cells and tissues in living beings contain thousands of proteins, with varied and specific functions (e.g., hormones, enzymes, structural proteins such as collagen, and tubulin, which constitutes the “skeleton” of cells and is responsible for their shape). In Alzheimer’s disease, some of these proteins become abnormal and accumulate.
The first type of protein deposit identified in the brain of patients affected by the disease contains a protein called “Tubulin-associated unit” or “Tau”. Normally, one of its functions is to stabilize the structure of neurons. In Alzheimer’s disease, Tau is modified and no longer plays its role. The neurons degenerate and abnormal proteins aggregate and accumulate within nerve cells.
The second type of deposit is formed by peptide beta-amyloid, or Aβ (like proteins, peptides are chains of amino acids, yet much shorter). The Aβ peptide is the result of a large protein called APP after it has been cut. Located on the surface of neurons, APP is involved in their growth, survival and repair.
Normally, Aβ peptides are eliminated, but in Alzheimer’s disease, they accumulate outside nerve cells as amyloid plaques, also sometimes called senile plaques. These deposits also develop around the blood capillaries of the brain and can cause cerebral microhaemorrhages called cerebral amyloid angiopathies.
Formation of amyloid plaques. Wikimedia, CC BY
Proteins with the ability to contaminate others
The most remarkable aspect of the mechanisms underlying Alzheimer’s is that neurodegeneration is not simply caused by the passive accumulation of proteins.
In fact, the proteins involved in Alzheimer’s disease change shape, which affects their mode of action at the cellular level. It is important to note that the role of a protein usually depends on its shape (which itself depends largely on the sequence of amino acids that compose it). This change in morphology confers on Aβ peptides properties that differ completely from those of its normal form. Once it becomes capable of self-aggregation, it can form deposits of amyloid fibres that are suspected to cause neuron death.
But that’s not all; as the researchers have shown, toxic forms are able to force their “normal” alter egos to imitate them and to adopt a pathogenic form as well. This phenomenon, known as “self-replication””, explains how a sick cell producing the toxic form of the peptide can “contaminate” the next cell.
Such contagion from one cell to another also explains why, during the development of Alzheimer’s disease, damage gradually spreads to the entire brain following a well-defined pattern in all patients.
What is Alzheimer’s disease?
Mechanisms that have similarities with prions
This self-replicating process is somewhat similar to what is observed in the case of Creutzfeldt-Jakob’s, another neurodegenerative disease. The latter is due to a very specific pathogen spreading in the brain: the prion.
Although it’s not a bacterium, a parasite, a virus or a fungus, the prion is nevertheless transmissible. The discovery of these proteinacious infectious particles, or “prions” generated considerable commentary and forced the researchers to come up with the new concept of “unconventional transmissible agents.” Unlike other pathogens, prions do not have a genome (i.e., no DNA or RNA) and they are composed exclusively of a single protein.
As is the case for the proteins involved in Alzheimer’s disease, cells naturally produce a “normal” version of the prion. Although it is believed to perform many biological functions, its full effect on the body is still poorly understood. It also has the property of folding and aggregating to form infectious particles. In their infectious form, prions are capable of infecting a new individual after, for example, the ingestion of contaminated tissues, or via the bloodstream.
The high resistance of prions to conventional destruction processes has caused several major economic and public health crises, such as the mad cow crisis in the 1980s and 1990s and the contaminated growth hormone scandal.
Is Alzheimer’s disease contagious?
The aggregation processes of the peptide Aβ and the Tau protein are similar to those observed in prions. So could Alzheimer’s disease be transmitted between individuals through the same mechanism as prions? Several teams of scientists have sought to answer this question.
Experimentally, several teams of researchers have been able to induce the proliferation of aggregates of peptide Aβ in lab animals. Additionally, more recent studies suggest the existence of cases of iatrogenic transmission of pathogenic Aβ peptide, causing cerebral amyloid angiopathies. Growth hormones produced before 1977, in particular, were not only contaminated by the prion, but also by the peptide Aβ, and they may have been involved in the development of Alzheimer’s disease.
As these studies were being published, another population called “at risk” has been documented in detail—that of patients who received a dura mater transplant. This thin, fibrous membrane that protects the brain was once removed from corpses to serve as a “bandage” after invasive neurosurgical operations. This practice was prohibited in France in 1994, after dura mater transplants have been found responsible for the iatrogenic transmission of the human prion.
Three studies (by Swiss, Japanese and international teams) have shown that 71.4%, 81% and 61.5 % of patients, respectively, who received this type of transplant later developed cerebral amyloid angiopathies. Although no formal evidence of graft contamination could be provided, the location of the lesions and protein deposits strongly suggests that the graft was responsible for the modification in shape and aggregation of the recipient’s Aβ peptides.
One study also suggested that the surgical instruments used in neurosurgery may also sometimes constitute a contamination source, although the risk is probably very limited. The authors of that study nevertheless encourage the medical profession to improve sterilisation procedures.
Is Alzheimer’s a prion disease?
From a purely mechanistic perspective, it seems clear that Alzheimer’s disease is similar to prion diseases. According to the strict definition of the word prion, or proteinacious infectious particle, Alzheimer’s disease should be considered as a prion disease, since the transmissible nature of the toxic protein assemblies responsible for the disease has been demonstrated, at least experimentally.
However, recent scientific advances have led to a broader concept of the prion, especially since different prion strains have been revealed, along with the prion’s ability to “mutate” and adapt to its new host. In this respect, prion diseases differ from Alzheimer’s disease. The current state of knowledge suggests that a more accurate description of Alzheimer’s would be to call it a “disease of the prion type” or to refer to the concept of “infectious amyloids”—or to include the protein assemblies responsible for Alzheimer’s disease under the concept of “unconventional transmissible agent.”