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
- Alzheimer’s Disease Awareness Month: What causes it? Experts say it may be a mix of multiple risk factorson November 20, 2020 at 12:53 am
Scientists are constantly learning but they do not yet completely understand what causes Alzheimer’s disease in most people. The causes probably include a combination of age-related changes in the ...
- Menuon November 19, 2020 at 3:59 pm
according to the Alzheimer’s Association Signs of early onset Alzheimer’s can show between the ages of 30 and 60 while late-onset symptoms generally show in a person’s mid-60s. There are certain ...
- A genetic link to molecular events that precede symptoms in Alzheimer's diseaseon November 19, 2020 at 12:23 pm
Researchers find a key mutation causing abnormal transport of BACE1, the enzyme responsible for processing the Alzheimer's disease-linked amyloid protein. Identification of this mutation, which is ...
- Air Pollution May Harm Older Women's Brainson November 19, 2020 at 7:34 am
(HealthDay News) -- Pollutants in the air -- fine particulates that are 30 times smaller than the width of a strand of hair -- may be damaging older women's brains. In a new study, researchers linked ...
- Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer’s disease trigger BACE1 accumulation in axonal swellingson November 18, 2020 at 12:35 pm
Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer’s disease (AD ... Gga3 genetic deletion or a GGA3 rare variant that cosegregates with late-onset AD, disrupts ...
- Found: a genetic link to molecular events that precede symptoms in Alzheimer's diseaseon November 18, 2020 at 11:09 am
The study, published today in Science Translational Medicine, reports that a human mutation more prevalent in African American patients with late onset Alzheimer's triggers a traffic jam of BACE1 ...
- Late-Onset Epilepsy Tied to a Threefold Increased Dementia Riskon November 10, 2020 at 2:13 pm
Late-onset epilepsy is linked to a substantial increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a ...
- Passage Bio, Inc. (PASG) CEO Karl Bruce Goldsmith on Q3 2020 Results - Earnings Call Transcripton November 10, 2020 at 10:50 am
On today's call, we'll mostly focus on where we stand with our three lead programs in GM1 gangliosidosis, frontotemporal dementia and ... escalation cohorts for late onset infantile GM1 and ...
via Bing News