Will Alzheimer's disease stop the correction of the ApoE4 protein?
ApoE is an ideal target for stopping the progression of Alzheimer's disease
LifeSciencesToday by Gladstone Institutes –
Gladstone Scientists: “ApoE Is an Ideal Target for Halting Progression of Alzheimer’s Disease”Despite all the efforts of scientists, there are no drugs that can reverse, stop or at least slow down the development of Alzheimer's disease.
A progressive neurodegenerative disease, Alzheimer's disease has deprived millions of people of their memories and livelihoods, forcing patients and their families to struggle with the terrible consequences of this disease. Gladstone Institute scientists propose a new research direction, possibly capable of changing the situation for the better.
In the journal Neuron, available online, Robert Mahley, MD, PhD, and Yadong Huang, MD, PhD, describe – at the molecular and cellular level – the process by which the development of Alzheimer's disease is promoted by an important protein known as ApoE4, and present a new strategy, which can radically change the course of disease progression (Apolipoprotein E Sets the Stage: Response to Injury Triggers Neuropathology).
Today, more than 5.4 million Americans suffer from Alzheimer's disease, with annual healthcare costs of up to $200 billion. According to experts, by 2050 the number of such patients will reach 16 million, and the financial costs of their treatment and maintenance will exceed $ 1 trillion. However, the most alarming is the fact that clinical trials of all drugs for the treatment of Alzheimer's disease, without exception, including those that proved to be promising in preclinical studies, ended in failure. The reason for this bleak situation, according to Dr. Mali and Juan, is that scientists do not take into account all possible biological targets.
"Most of the research is focused on two key proteins associated with Alzheimer's disease – beta-amyloid and tau," says Dr. Mali, honorary president of the Gladstone Institute and a member of the team of scientists who discovered AoE. "Beta-amyloid and tau do accumulate in the brains of such patients, but Alzheimer's disease is a complex disease with many molecular players. Given that clinical trials of drugs targeted at beta-amyloid and tau have so far failed, it's time to direct our energy to ApoE4."
The ApoE4 protein is encoded by the gene with the same name – ApoE4. There are two more types, or variants, of AoE – apoE2 and apoE3 – each of which has its own effect on the development of the disease. However, unlike the other two variants, ApoE4 has long been associated with an increased risk of developing Alzheimer's disease. So, while a variant of the ApoE4 gene is present in the genome of every fourth person, in patients with Alzheimer's disease it occurs with a frequency of 65-80%. In addition, ApoE4 is involved in the development of other neurological diseases, including Parkinson's disease and multiple sclerosis, and also significantly correlates with poor clinical outcome in traumatic brain injuries.
Nevertheless, although ApoE4 is associated with a number of diseases, ApoE4 itself plays an important role in normal brain activity.
"The AroE protein is fundamentally important because it helps to eliminate damage to brain cells," explains Dr. Huang, co–author of the article, associate professor of neurology and pathology at the University of California, San Francisco (UCSF), of which the Gladstone Institute is affiliated. "When brain cells, or neurons, are damaged as a result of trauma, stress, or in the process of normal aging, they synthesize aroE to eliminate these damages faster."
However, the nature of the folding of the ApoE4 variant – unlike apoE2 or apoE3 – is such that it can lead to serious problems.
On the diagram from the Huang lab page from the Gladstone Institute website –
structural schemes of molecules of "pathological" ApoE4 and "normal" apoE3
The synthesis of ApoE4 in neurons is the trigger of a chain of events that, over time, sometimes leads to degeneration and death of neurons. For example, there is evidence that during the synthesis of ApoE4, one of the enzymes cuts off part of the protein, creating fragments of ApoE4 that disrupt the normal functioning of the cell. As a result, pathological forms of tau protein accumulate in neurons, which further aggravates the condition of nerve cells.
In addition, ApoE4 disrupts the normal process of removing excess beta-amyloid. As a result, beta-amyloid continues to accumulate to a toxic level, further disrupting the functions of neurons. This complex and multi-stage cascade may explain why all drugs that target only beta–amyloid or tau have failed - they do not affect the underlying problem of ApoE4.
"Even with drugs capable of removing beta-amyloid and tau from the cell, we still preserve the soil for the development of the disease, allowing improperly folded aroE proteins to continue their work unhindered," concludes Dr. Mali, professor of pathology and medicine at UCSF. "But if we switch our efforts to developing drugs that correct the form of the ApoE4 protein, we will have a real chance to slow down or even stop the disease. To this end, we have developed drugs, the so-called ApoE4 structure correctors, capable of turning pathological ApoE4 into a molecule that is structurally and functionally close to the so-called "normal" apoE3 protein."
"In this generalizing and comprehensive study, Dr. Mali and Juan – true leaders in the field of aroE and Alzheimer's disease – remind us that we must take into account all known aspects of this terrible disease," comments Lennart Mucke, MD, head of neurological research at Gladstone. "I hope that by joining the efforts of Gladstone scientists and researchers around the world, we are now closer than ever to developing treatments that will really make a difference for patients and their families."
Portal "Eternal youth" http://vechnayamolodost.ru15.01.2013