We Must Take a More Intelligent Approach to Dementia
Emerging evidence suggests that Alzheimer’s-related brain changes may result from a complex interplay among abnormal tau and beta-amyloid proteins and several other factors. It appears that abnormal tau accumulates in specific brain regions involved in memory. Beta-amyloid clumps into plaques between neurons. As the level of beta-amyloid reaches a tipping point, there is a rapid spread of tau throughout the brain.
… People with dementia seldom have only Alzheimer’s-related changes in their brains. Any number of vascular issues—problems that affect blood vessels, such as beta-amyloid deposits in brain arteries, atherosclerosis (hardening of the arteries), and mini-strokes—may also be at play.
… In Alzheimer’s disease, as neurons are injured and die throughout the brain, connections between networks of neurons may break down, and many brain regions begin to shrink. By the final stages of Alzheimer’s, this process—called brain atrophy—is widespread, causing significant loss of brain volume. __ https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease
US Dementia to Double by 2060
Aging populations and Alzheimer’s
Dementia rates rise as a population ages. The root causes of human dementia are not clearly understood, although chronic inflammation, vascular disease, and genetic defects are all considered important parts of the puzzle.
Beta Amyloid: Wildfire in the Brain
Abnormal beta amyloid accumulation in the brain is a likely part of the causation ensemble. But so far, none of the drugs designed to reduce beta amyloid levels have been effective in treating Alzheimer’s.
A new study could help explain this string of drug failures, discovering that when a synapse in the brain is destroyed by beta-amyloid it triggers nearby nerve cells to produce more beta-amyloid. This sets off a feedback loop that drives further neurodegeneration.
“We show that a vicious positive feedback loop exists in which beta-amyloid drives its own production,” says Richard Killick, senior author on the new study. “We think that once this feedback loop gets out of control it is too late for drugs which target beta-amyloid to be effective, and this could explain why so many Alzheimer’s drug trials have failed.”
The research reveals that a protein called Dkk1 is fundamental to this damaging feedback loop. The protein has been found to significantly stimulate production of beta-amyloid and it appears in increasing volumes in the brain as we age. __ https://newatlas.com/alzheimers-amyloid-feedback-fasudil/56442/
If beta amyloid’s out of control “wildfire” positive feedback destruction in the brain can be slowed by interfering with the protein Dkk1 — or other brain chemicals that have similar effects — drug designers will have a better target to aim at.
But even a perfect cleanup of beta-amyloid is not likely to be enough:
… some research has suggested clearing beta-amyloid deposits does not always correlate with improvements in cognition, meaning that although this new research is interesting, it doesn’t necessarily mean it will correspond with cognitive improvements in humans. __ https://newatlas.com/alzheimers-amyloid-feedback-fasudil/56442/
Scientists need to expand their vision of Alzheimer’s to include multiple causes.
Tau Proteins, Neurotangles, Cleaning Up Zombie Cells
Going beyond beta amyloid, another likely causative agent in Alzheimer’s is the tau proteins. Tau protein accumulation leads to neurofibrillary tangles, which are deadly to neurons. Scientists are discovering that one way to limit tau protein damage may be by cleaning out the “zombie cells of senescence” which accumulate in the brain with age.
The latest study set out to examine the role of senescent cells in the progression of neurodegenerative disease. The team experimented with two different methods to clear senescent cells in mouse models. One method utilized a genetically engineered mouse designed to imitate Alzheimer’s disease pathology by producing tangles of tau proteins in their neurons. This mouse model was subsequently engineered to be able to effectively clear senescent cells from its system when a specific chemical trigger was introduced.
“When senescent cells were removed, we found that the diseased animals retained the ability to form memories, eliminated signs of inflammation, did not develop neurofibrillary tangles, and had maintained normal brain mass,” reveals Tyler Bussian, first author on the new study.
The other experiment found a novel experimental anticancer drug called navitoclax also functions as an effective senolytic agent, removing senescent cells from the mouse brains and successfully modulating the accumulation of tau proteins.
This novel discovery uncovers an exciting causal link between cellular senescence in the brain and the onset of neurodegenerative pathology. Even more interesting was the revelation that it wasn’t the specific neurons becoming senescent that was preceding the tau protein clumping, but two other kinds of senescent brain cells – microglia and astrocytes.
Microglia and astrocytes are glial cells, normally meant to assist, nourish and protect neurons, and clean up the neuronal environment. Something happens in the pre-dementia state to cause glial cells to malfunction.
Chronic Inflammation, Gene Defects, and Glial Cell Dysfunction
Research suggests that chronic inflammation may be caused by the buildup of glial cells normally meant to help keep the brain free of debris. One type of glial cell, microglia, engulfs and destroys waste and toxins in a healthy brain. In Alzheimer’s, microglia fail to clear away waste, debris, and protein collections, including beta-amyloid plaques. Researchers are trying to find out why microglia fail to perform this vital function in Alzheimer’s.
One focus of study is a gene called TREM2. Normally, TREM2 tells the microglia cells to clear beta-amyloid plaques from the brain and helps fight inflammation in the brain. In the brains of people where this gene does not function normally, plaques build up between neurons. Astrocytes—another type of glial cell—are signaled to help clear the buildup of plaques and other cellular debris left behind. These microglia and astrocytes collect around the neurons but fail to perform their debris-clearing function. In addition, they release chemicals that cause chronic inflammation and further damage the neurons they are meant to protect. __ https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease
Something happens to glial cells to prevent them from performing their neuroprotective tasks. They are somehow turned into “homicidal maniacs” for a while, causing additional inflammation and nerve damage — until they die and become damaging brain debris themselves.
More to Alzheimer’s than Once Thought
Current drugs to treat Alzheimer’s do not stop or reverse cognitive decline. It is likely that drug designers have been aiming at the wrong target — or perhaps not aiming at enough of the right targets.
Instead of fixating on one theory, good scientists go back to basics when first attempts fail. The dementia universe is growing larger, making it more important for scientists and clinicians to expand their conceptual space.
Update: Leaky blood brain barrier likely part of the puzzle. A leaking blood brain barrier is both a marker for inflammatory vascular damage and a cause of further inflammation in the brain beyond the barrier.
Scientists at the Al Fin Institutes for Longevity and Life Extension have long recommended the daily use of alpha lipoic acid along with other anti-inflammatory supplements that exert a protective action against inflammation and oxygen radicals, such as TMG.