How does Alzheimer's disease begin?

Back to the beginning

Early synapse loss in Alzheimer's disease can be prevented

LifeSciencesToday based on materials from Harvard Medical School: Back to the Beginning

Scientists from Harvard Medical School have found the cause of synapse loss at an early stage of Alzheimer's disease and proved that this process begins before the formation of beta-amyloid plaques in the brain. Their work, published in the journal Science (Hong et al., Complement and microglia mediate early synapse loss in Alzheimer mouse models), provides new therapeutic targets for preserving cognitive functions at an early stage of this neurodegenerative disease.

In several mouse models of Alzheimer's disease, scientists have shown that mechanisms similar to those that remove excess synapses in a healthy developing brain are mistakenly activated in old age. By blocking these mechanisms, scientists partially stopped the loss of synapses in animals.

To date, there are five FDA-approved drugs for the treatment of Alzheimer's disease, but all of them can only temporarily improve cognitive abilities and do not affect the causes of their decline. The targets of many new drugs are accumulations of beta-amyloid and inflammation, but a new study shows that Alzheimer's disease can be affected much earlier, before the appearance of these pathological changes.

"The loss of synapses strongly correlates with a decrease in mental abilities," says the head of the study, Professor of neurology Beth Stevens, PhD. "We're trying to go back to the beginning and find out how synapse loss begins."

Professor Stevens and her colleagues looked at Alzheimer's disease through an unusual prism – normal brain development in infancy and childhood. For many years, the Stevens laboratory has received confirmation that during the formation of neural networks in a normally developing brain, the process of removing unnecessary synapses is underway.

"A deep understanding of the normal process of development has given us new ideas on how to protect synapses in Alzheimer's disease and possibly in a number of other diseases," says Dr. Stevens, noting that synapse loss is also characteristic of frontotemporal dementia, Huntington's disease, schizophrenia, glaucoma and other diseases.

In mice with an Alzheimer's disease model, the researchers showed that synapse loss requires activation of the C1q protein, which marks synapses that need to be removed. Then microglia – the immune cells of the brain – "eats" synapses, just as it happens during the normal development of the brain. In mice, the amount of C1q protein near vulnerable synapses increases before beta-amyloid deposits appear. Blocking C1q, the underlying C3 protein, or the C3 receptor on microglial cells stops synapse loss.

The complement protein C1q (green) marks synapses (red) in mice with an Alzheimer's disease model. The yellow dots are an overlap of C1q and the postsynaptic protein PSD95, indicating synapses. These mice have more C1q-labeled synapses than their healthy littermates. (Photo: Soyon Hong).

"The involvement of microglia and complement in Alzheimer's disease is already known, but it was most often considered as a secondary event related to the inflammation associated with beta-amyloid plaques, a characteristic feature of the later stages of Alzheimer's disease. Our study challenges this opinion and indicates that complement and microglia are involved in this pathological process much earlier, when synapses are already vulnerable, and can potentially be targets for synapse preservation," explains the significance of his work, the first author of the article Soyoun Hong, PhD, researcher at HMS.

Microglia (red) "devours" synapses (green) after administration to mice
oligomeric form of beta-amyloid before the appearance of plaques in the brain.
(Video: Soyon Hong, Boston Children's Hospital).

The human analogue of the antibody that Stevens and Hoon used to block C1q, known as ANX-005, is in the early stages of therapeutic development at Annexon Biosciences (San Francisco). The necessary preliminary work is carried out before clinical trials. Researchers believe that this antibody has the potential to be used to protect against synapse loss in various neurodegenerative diseases.

"This study highlights the need to search for biomarkers of synapse loss and dysfunction," Dr. Hong continues. "As with cancer, if treatment begins at a later stage of Alzheimer's disease, it may be too late."

Scientists have also found that beta-amyloid is involved in the process of synapse loss in the early stages of Alzheimer's disease, along with the C1q protein and microglia.

The oligomeric form of beta-amyloid (a molecule consisting of several monomers) has long been known for its toxicity to synapses, even before the formation of plaques, but a study by Stevens and Hoon showed that C1q is needed to realize this effect. The opposite is also true: microglia "devours" synapses only in the presence of beta-amyloid oligomers.

Portal "Eternal youth" http://vechnayamolodost.ru  08.04.2016