UTSW researchers neutralize genetic risk factor found in 50 to 80 percent of human cases
UT Southwestern researchers have succeeded in neutralizing what they believe is a primary factor in late-onset Alzheimer’s disease, opening the door to development of a drug that could be administered before age 40, and taken for life, to potentially prevent the disease in 50 to 80 percent of at-risk adults.
Apolipoprotein E (ApoE) is a protein that carries fatty substances called lipids and cholesterol around the brain and plays an important role in repair mechanisms. There are three major forms of ApoE (i.e., ApoE2, ApoE3, and ApoE4); individuals who carry ApoE4 are up to 10 times more likely to develop Alzheimer’s than those with ApoE2 and ApoE3 forms. ApoE4 promotes accumulation of the b-amyloid protein that causes the characteristic plaques seen in the brains of Alzheimer’s patients.
UT Southwestern molecular biologist and Alzheimer’s expert Dr. Joachim Herz, lead author of the study, which was published in the November issue of eLife said the goal of his team is to prevent the disease from ever manifesting. Late-onset Alzheimer’s generally is diagnosed about age 65 and is the most common cause of dementia in the elderly. “If we can negate the ApoE4 process early, we may be able to prevent late-onset Alzheimer’s altogether for many people so that they will never get sick,” Dr. Herz said.
ApoE4 has been shown to suppress and trap synaptic receptors within intracellular vesicles. However, how the ApoE4 gets trapped has remained a mystery until now. According to Dr. Herz, ApoE4 is the root cause of a “traffic jam” inside the cells that take up ApoE4 and this is associated with reduced recycling of intracellular endosomal transport vesicles. UTSW researchers found that lowering the pH of these endosomes, i.e., by making them more acidic, cleared the traffic jam: The scientists were able to completely reverse the ApoE4-induced recycling block in mice through pharmacological and genetic inhibition of the NHE6 protein, which acts to make the endosomal vesicles less acidic.
These findings suggest a novel potential therapeutic approach for the prevention of late-onset Alzheimer’s disease, Dr. Herz said. The vesicle traffic jam due to the selective loss of solubility of ApoE4 likely is the earliest mechanism at which the protein negatively affects nerve cells, Dr. Herz said.
Most Alzheimer’s research has focused on halting the formation of amyloid and tau protein aggregates once they exist in the brain and degeneration has already begun. “Our approach in this study was to stop the overall degeneration process earlier; that is, before the formation of these aggregates,” Dr. Herz said.
The next step is to develop tailor-made, small molecule inhibitors that can enter the brain efficiently and selectively block NHE6, he added.
“The beauty of NHE inhibitors is that these are small molecules that can be produced inexpensively and thus made widely available, in contrast to the more elaborate antibody-based therapies that are currently being evaluated in clinical trials. A simple pill could someday neutralize the risk of late-onset Alzheimer’s disease just as readily available statins are able to reduce the risk of cardiovascular disease,” Dr. Herz said.
The Latest on: Late-onset Alzheimer’s
via Google News
The Latest on: Late-onset Alzheimer’s
- APOE4 carriers with longevity-gene variant have lower Alzheimer's riskon May 8, 2020 at 7:05 am
The risk of developing Alzheimer's disease among people who carry the genetic risk factor apolipoprotein E4 (APOE4) appears to be lower in those who are also heterozygous for the Klotho functional ...
- Causal Link between Alzheimer’s Disease and Herpes Simplex Virus Type 1 Identified Using 3D Human Tissue Modelson May 7, 2020 at 5:00 am
Researchers suggest their bioengineered tissue and findings model could lead to the development of therapeutic strategies for treating Alzheimer's Disease ...
- Myths About Alzheimer’s Disease You Should Stop Believingon May 6, 2020 at 2:44 am
"We all have a 50 per cent chance of developing Alzheimer’s disease after age 85. Most people diagnosed with late-onset Alzheimer’s disease do not test positive as carriers for any of the ...
- Plasma Cholesterol and Risk for Late-onset Alzheimer's Diseaseon May 5, 2020 at 5:00 pm
An apparent contradictory observation in the study is that not only low HDL-C, but also low non-HDL-C levels, are associated with higher AD risk. It could be expected that high non-HDL-C would ...
- UO lab looking at aging arteries and Alzheimer’s diseaseon May 5, 2020 at 5:47 am
University of Oregon scientist Ashley Walker focuses on what happens as arteries stiffen with age, research that has led to possible connections to Alzheimer’s disease. Walker, who joined the ...
- Plasma Cholesterol and Risk for Late-onset Alzheimer's Diseaseon May 4, 2020 at 5:00 pm
Alzheimer's disease (AD), the most common ... experimental and clinical data strongly suggest that the metabolism of cholesterol has an important role in AD pathogenesis. Several studies have ...
- One Gene Is a Major Risk Factor For Alzheimer's Disease, And We May Finally Know Whyon May 4, 2020 at 12:48 pm
New research has revealed that a gene variant known to be a major risk factor for Alzheimer's disease can predict the decline of mental capacities separately from the protein tangles involved in the ...
- New study says this is the only diet that will keep your brain healthy for years to comeon April 28, 2020 at 2:54 pm
According to a new study, a diet rich with vegetables, fruits, legumes, fish, olive oil, and nuts dramatically reduces one’s risk of developing neurodegenerative diseases later in life.
- NIH Distributes $45 Million for Alzheimer's Researchon April 27, 2020 at 5:00 pm
At Mount Sinai, the NIH grant will enable the research team and partner institutions to build upon the discovery published earlier this year in the journal Cell of a network of genes as a key ...
- Dementia Patients Aren’t in Their ‘Perfect Mind.’ Then Again, Who Is?on April 21, 2020 at 10:40 am
While working on the book, she learned that both of her parents carry one copy of a gene variant linked to late-onset Alzheimer’s disease: “I have a 50 percent chance of having a single copy ...
via Bing News