A team of scientists from the University of Southern California (USA) has discovered, in a study with mice, a process that precedes the accumulation of toxic proteins in the brain , a hallmark of Alzheimer’s disease. Experts reveal how damage to cells called pericytes can trigger white matter disease, which is associated with dementia. As if this weren’t enough, the study’s findings suggest that these brain changes can occur by the age of 40.
According to study lead author Berislav Zlokovic, Alzheimer’s is a gray matter disease, but white matter damage plays a key role in how the disease attacks and progresses in the brain. According to the researchers, “ White matter disease contributes to nearly 50% of dementia cases worldwide , including Alzheimer’s disease.”
However, the precise mechanisms by which white matter disease can lead to dementia are unclear. Here comes the new study published in the journal N ature Medicine.
The study focused on the role of pericytes , which are the cells that line the walls of capillaries, or the smallest blood vessels in the body. First, they conducted a post-mortem analysis of the brains of people with Alzheimer’s disease and compared them to the brains of healthy adults.
The researchers found that the brains of people with Alzheimer’s disease had 50% fewer pericytes than healthy brains, and levels of a protein called fibrinogen, a circulating protein that helps wound healing, tripled in the regions of white matter.
By using MRI to study mouse models that were deficient in pericytes, these cells were found to play a key role in white matter health.
When pericyte-deficient mice were 12 to 16 weeks old, which equates to about 40 years in humans, their fibrinogen levels were about 10 times higher in the corpus callosum, a brain region that plays a role. in the transmission of cognitive and sensory data from one side of the brain to the other.
At 36-48 weeks of age – the equivalent of 70 human years – pericyte-deficient mice demonstrated a 50% increase in blood vessel leakage.
“Our observations suggest that once the pericytes are damaged, blood flow in the brain is reduced like a slowly clogged drain,” explains Angeliki Maria Nikolakopoulou, leader of the work.
Discovering ‘the beginnings of dementia’
For the next part of the study, the team evaluated the rodents’ running speed using a wheel test. When they reached 12-16 weeks of age, pericyte-deficient mice were found to run 50% slower than control mice.
“Mice deficient in pericytes function more slowly because there are structural changes in their white matter and a loss of connectivity between neurons,” says Zlokovic.
According to experts, this finding indicates that in humans, white matter disease could begin as early as the age of 40.
“Many scientists have focused their research on Alzheimer’s disease on the accumulation of toxic amyloid and tau proteins in the brain, but this study and others from my laboratory show that the problem begins much earlier,” says Zlokovic.
A new approach to preventing dementia?
When the researchers used a compound to reduce fibrinogen levels in the rodents’ blood and brain, they found that white matter volume was restored to 90%, while white matter connectivity was restored to 80%.
“Our study provides evidence that attacking fibrinogen and limiting these protein deposits in the brain can reverse or slow down white matter disease,” concludes Zlokovic.
Referencia: Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Neurology 2018. DOI: https://doi.org/10.1016/S1474-4422(13)70124-8
