The "Vicious Cycle" of Alzheimer's Disease

One of the first molecular characteristics of Alzheimer’s disease is the aggregation of a protein called β-amyloid peptide (Aβ) in regions of the brain responsible for memory and cognition.

These aggregations can form physical plaques that interfere with cell communication, ultimately leading to brain cell death and the pathophysiology behind Alzheimer's disease. 

The precise mechanisms behind Alzheimer's disease pathology have been evasive

Despite many decades of research on this protein, scientists still do not know exactly how these aggregations arise and how it is involved in the progression of the disease. Many studies that have reduced or removed the presence of Aβ in the brains of mice have failed to slow the symptoms of the disease.

Results like these are the reason why finding therapeutic solutions have been so difficult to find. The progression of the disease appears to be independent of the molecular pathology that characterizes it.  

In a study published this year by Zott et al., researchers have found the first signs of how Aβ can interfere with cell to cell communication which leads to a “vicious cycle” of more interference leading to the progression of Alzheimer’s Disease.

β-amyloid creates a self-perpetuating cycle of neuronal hyperactivation

In this new study, researchers showed that Aβ presence led to interference in neuron communication, specifically hyperactivity in the synapse. This hyperactivity is brought about by imbalances in one of the main excitatory neurotransmitters in the brain, glutamate. When glutamate uptake is impaired by beta-amyloid peptide, the neurotransmitter cannot be recycled, leading to its accumulation within the synapse.[1]  

This hyperactivity leads to even more Aβ accumulating around the cells and further dysfunction in neuronal communication. Brain samples from both humans and mice show that this vicious cycle leads to a large amount of Aβ present which may contribute towards explaining the perceived pathological nature of Alzheimer’s.

Hyperactivity from excessive glutamate may be an important early disease feature for future Alzheimer's detection and treatment

This is important in the field of Alzheimer’s research because it shows a promising window for future treatments. It’s critical to detect and treat the disease as early as possible, prior to the development of significant memory loss.  

Since their results suggest that this vicious cycle begins with hyperactivity in the cell, drugs that specifically reduce cell activity, such as drugs that reduce glutamate levels, could possibly be used.[2]

Also, the molecular mechanisms outlined in this paper precede any characteristics of AD, long before any symptoms of the disease are shown. If pharmaceuticals could intervene at this point, the progression of AD could slow down or even stop. There are still many unknowns about how AD advances as a disease but this paper may lead to more breakthroughs in the future. 

References

1. B. Zott et al.,A vicious cycle of β amyloid–dependent neuronal hyperactivation. Science 365, 559 (2019)

2. Selkoe, D.J. Early network dysfunction in Alzheimer's disease. Science 365, 540 (2019)