Electron microscope image of an amyloid plaque and tau fibers (dark pink lines) in the brain of … [+]
Neurologists have discovered a genetic mutation that may protect the brain against dementia.
Francisco Lopera, a researcher at the University of Antioquia in Colombia, has spent nearly 40 years studying a family of individuals with a rare form of early-onset Alzheimer’s disease that causes them to develop symptoms of dementia when they enter the being forty. The early form of Alzheimer’s disease is believed to be caused by the Paisa genetic mutation and is found in many of the 6,000 family members.
Now Lopera has identified one family member who carries a second unique genetic mutation that has somehow protected him from dementia until he is 67 years old. Interestingly enough, despite his cognitive abilities, the patient carries the paisa mutation and shows other biomarkers for Alzheimer’s disease, such as amyloid plaques.
This study not only challenges the theory that amyloid plaques are the primary cause of Alzheimer’s disease symptoms, but also points to a possible treatment route for Alzheimer’s disease. The question that remains is: what is this genetic mutation and how does it protect the brain against dementia?
This story starts with the paisa mutation. The paisa mutation is named after people from the Antioquia region of Colombia and is one of the most common genetic causes of early Alzheimer’s disease. The mutation affects the PSEN1 gene that codes for a protein called presenilin 1. Presenilin 1 is part of a protein complex called gamma-secretase that is responsible for cutting other proteins into smaller pieces.
The gamma-secretase complex plays a critical role in Alzheimer’s disease by cleaving amyloid precursor protein. When the PSEN1 gene is mutated, the gamma-secretase complex tends to cut the amyloid precursor protein into slightly longer pieces. These longer chains of amyloid protein eventually aggregate and form amyloid plaques in the brain.
This mutation and its effects on the development of amyloid plaques are believed to cause many people in Antioquia, Colombia, to develop early-stage Alzheimer’s disease. However, Lopera’s research now suggests that there may be more to the story of Alzheimer’s disease and dementia than just amyloid plaques.
Lopera and his research team approached their study by analyzing the genetic makeup of the 1,200 individuals within a Colombian family lineage that paisa mutation. By studying the genetic makeup and profiles of the 1,200 individuals, they identified a subject who, unlike his relatives, remained completely cognitively intact until age 67.
After imaging the man’s brain, researchers found that he had significantly more amyloid plaques despite his cognitive abilities. The researchers also examined another biomarker for Alzheimer’s disease: tau tangles. Tau is another protein that tends to aggregate in Alzheimer’s disease patients, leading to obvious tangles in the brain.
Interestingly, while the man showed higher levels of tau tangles in most of the brain, a certain area called the entorhinal cortex was unharmed. The entorhinal cortex is believed to play an important role in learning and memory and is usually significantly damaged in people with severe Alzheimer’s disease.
This led to an important question: How could the man maintain his cognitive abilities despite clear indicators of Alzheimer’s disease in his brain? Analysis of the man’s genetic makeup revealed that he contained a unique genetic mutation that affected his production of a protein called reelin.
In the adult brain, reelin is known to support the storage of long-term memories by protecting the formation of synapses – the connections between neurons. It also stimulates the growth and spread of neurons. While studies have shown that genetic mutations that reduce reelin production may increase the risk of schizophrenia and autism, very little is known about the protein’s role in neurodegenerative diseases such as Alzheimer’s disease.
To investigate reelin’s role and how the genetic mutation may affect cellular function in the brain, Lopera’s research team inserted the genetic mutation into mice. They found that the mutation increased reelin’s activity. In fact, the genetic mutation increased the number of neurons in the brains of male mice aged 6-12 months. This suggests that the reelin mutation may have a protective effect by promoting neuron growth and survival.
Lopera then assessed how the reelin mutation affected tau accumulation in the brain by introducing the reelin mutation into mice with the ability to develop phosphorylated tau. High levels of phosphorylated tau lead to an abundance of tau tangles. From this, they found that mice with the reelin mutation had a significant reduction in phosphorylated tau not only in the entorhinal cortex, but also in the hippocampus – a broader region of the brain responsible for learning and memory. Outside of the hippocampus, the researchers found that tau phosphorylation was also reduced in the medulla oblongata, which controls important processes such as heart rate, breathing and blood pressure.
When researchers examined the molecular structure and interactions of the mutated reelin protein, they discovered something interesting. The mutated reelin protein actually binds to the same receptor as the APOE protein. The APOE gene is one of the few known genetic risk factors for Alzheimer’s disease. The fact that both the mutated reelin and APOE bind to the same receptors suggests that there may be some shared mechanisms between the two proteins. In other words, a stronger protective reelin protein or a weaker APOE protein can protect against Alzheimer’s disease.
Lopera’s paper did not comment on the specific mutation in the reelin gene and how it may alter reelin’s structure to increase the protein’s activity. Dr. However, Roberto Patarca, the Chief Medical Officer of ACCESS Health International, suggests that the mutation may affect three regions of the reeling gene that allow reelin protein to bind to the APOE protein. Mutations in these regions could make reelin more effective at binding to the APOE receptor, allowing the protein to have greater protective effects against APOE in Alzheimer’s disease.
This study is not the first to identify individuals who have severe amyloid plaques but do not experience symptoms of dementia. However, this paper is an important stepping stone to pinpointing a genetic mutation that may be responsible for protecting the brain against dementia in the presence of plaques. While more research needs to be done to determine exactly how and why the reelin protein appears to affect tau tangles in the hippocampus, this unique case may indicate that reelin is a useful target of Alzheimer’s disease treatments.