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Heart Health Linked With Dementia Treatment

by Karishma Abhishek on Jun 21 2021 11:56 PM

Heart Health Linked With Dementia Treatment
High levels of a normal protein associated with reduced heart disease are shown to offer protection against Alzheimer's-like brain damage as per a study in mice at the Washington University School of Medicine in St. Louis, published in the journal Neuron.
Alzheimer's disease (AD) is a neurodegenerative disease that leads to gradual memory loss and behavioral changes. It is characterized by the formation of beta-amyloid plaques in the brain tissues, almost 20 years before the actual symptoms occur. This further leads to the shrinkage of the brain tissue.

Thus the cognitive decline occurring in the disease can be stopped by raising the levels of this heart protein ¡V low-density lipoprotein receptor (LDL receptor), thereby serving as a potential therapeutic target for dementia.

The LDL receptor has an important role in the regulation of cholesterol metabolism and is widely prescribed for cardiovascular disease. The drugs commonly used for increasing the levels of LDL receptors in the liver and some other tissues are statins and PCSK9 inhibitors. However, their effect is not known in the brain.

"There are not yet clearly effective therapies to preserve cognitive function in people with Alzheimer's disease. We found that increasing LDL receptor in the brain strongly decreases neurodegeneration and protects against brain injury in mice. If you could increase LDL receptor in the brain with a small molecule or other approach, it could be a very attractive treatment strategy," says senior author David Holtzman, MD, the Andrew B., and Gretchen P. Jones Professor and head of the Department of Neurology.

LDL and Alzheimer's disease

High levels of a protein ¡V APOE are linked to both cholesterol metabolism and Alzheimer's disease by driving tau-mediated degeneration in the brain through activation of microglia (brain¡¦s immune cells).

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Hence increasing the levels of LDL receptors may limit the damage that APOE can impart to the brain. The team thereby studied this association of LDL in the mice model of Alzheimer's-like neurodegeneration. The tau mice were bred with mice genetically modified mice that would express high levels of LDL receptors in their brains.

It was found that the resulting offspring had high levels of LDL receptor and a propensity to develop Alzheimer's-like brain damage by the time they were 9 months old, which is similar to middle age in a person.

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The four groups: normal mice, tau mice, mice with high levels of LDL receptor, and tau mice with high levels of LDL receptor were then compared. Severe brain atrophy and neurological damages were seen in the tau mice when compared to the healthy-looking brains of the normal mice and the mice with high levels of LDL receptor at 9 months of age.

Moreover, the tau mice with high levels of LDL receptor had less brain shrinkage and damage. The team also found that the levels of certain forms of tau and APOE were significantly lower, and their microglia was shifted toward a less damaging pattern of activation.

"Alzheimer's develops slowly through multiple phases, and the degeneration phase when tau is building up is when the symptoms arise and worsen. In terms of quality of life for people with Alzheimer's, this is a phase in which it would be great if we could intervene. I think this LDL receptor pathway is a good candidate because it has a strong effect, and we know it can be targeted in other parts of the body. This has motivated us over the last few years to try to develop programs to modulate the receptor in other ways," says Holtzman.

Source-Medindia


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