Alzheimer's remains the leading cause of dementia in Western societies, with some estimates suggesting that as many as 24 million people worldwide are living with the disease. Alzheimer's is characterized by a progressive decline in cognitive ability that eventually affects even basic functions such as walking and swallowing. The exact cause of Alzheimer's is unknown, but pathological changes in the brain, including neuron loss and an accumulation of protein aggregates called beta-amyloid plaques, are a diagnostic hallmark of Alzheimer's disease.
Mild cognitive impairment (MCI) describes the slight but measurable changes in cognitive function that are often a precursor to Alzheimer's disease. However, despite the importance of MCI, very little is known about the changes that occur in the brain during the progression from MCI to Alzheimer's.
In a recent study published in Nature Communications, researchers have now discovered that preventing pathological changes in the brain at the MCI stage could eliminate Alzheimer's disease altogether.
"Neuronal death, is obviously very important in the development of Alzheimer's, but is notoriously difficult to detect in real time because dying cells cannot be stained using chemical or immunohistological methods," says lead author of the study. "Because of this, we used a new biomarker called pSer46-MARCKS to detect degenerative neurites surrounding dying neurons, allowing us to quantify levels of necrosis, a prototype of neuronal death, at different stages of disease."
Surprisingly, the researchers found that neuronal death occurred much earlier than originally thought, with higher levels of necrosis seen in patients with MCI than in patients with full-blown Alzheimer's disease.
The researchers also observed a significant decrease in the levels of a protein known as YAP in Alzheimer's disease model mice and human patients with MCI. YAP positively affects the activity of a second protein called TEAD, a deficiency of which leads to neuronal necrosis. Microscopic examination revealed that the missing YAP was sequestered within beta-amyloid plaques, which have also been linked to neuronal toxicity.
By directly injecting a gene therapy vector expressing YAP analog into the cerebral spinal fluid of mice that were genetically engineered to provide a model of Alzheimer's, the researchers were able to prevent early-stage neuron loss, restore cognitive function, and prevent the development of beta-amyloid plaques.
"Confirming that neuronal necrosis was dependent on YAP was really the pivotal moment for us, but observing the almost transformative effects of YAP supplementation was hugely exciting," says senior author of the study. "By showing that neuronal necrosis is YAP-dependent and begins prior to the onset of most symptoms, we predict that novel Alzheimer's disease therapies will be developed to prevent the initiation of Alzheimer's disease."
"Another important issue is that the necrosis of neurons accumulating intracellular beta-amyloid occurs before formation of beta-amyloid plaques," continues the senior author. "Residual beta-amyloid after neuronal necrosis seems to be the seed for beta-amyloid plaques outside of neurons. This discovery might change the amyloid hypothesis considering that extracellular beta-amyloid plaque is the top of pathological cascade of Alzheimer's disease."
http://www.tmd.ac.jp/english/press-release/20200128_1/index.html
https://www.nature.com/articles/s41467-020-14353-6
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fyap-dependent-necrosis_2&filter=22
Early brain cell death uncovered in Alzheimer's
- 1,594 views
- Added
Edited
Latest News
TB blood test which could d…
By newseditor
Posted 27 Mar
Propionate supplementation…
By newseditor
Posted 27 Mar
Role of human Kallistatin i…
By newseditor
Posted 26 Mar
Addressing both flu and COV…
By newseditor
Posted 26 Mar
How the brain senses body p…
By newseditor
Posted 26 Mar
Other Top Stories
Attention recruits frontal cortex in human infants
Read more
Early life stress in neurons is mediated by epigenetic mechanism
Read more
Negative mood linked to prolonged amygdala activity
Read more
How the brain understands sentences
Read more
Does 'harsh parenting' lead to smaller brains?
Read more
Protocols
All-optical presynaptic pla…
By newseditor
Posted 23 Mar
Epigenomic tomography for p…
By newseditor
Posted 20 Mar
A mouse DRG genetic toolkit…
By newseditor
Posted 17 Mar
An optogenetic method for t…
By newseditor
Posted 13 Mar
Profiling native pulmonary…
By newseditor
Posted 08 Mar
Publications
Balancing neuronal activity…
By newseditor
Posted 28 Mar
OSBP-mediated PI(4)P-choles…
By newseditor
Posted 28 Mar
Integrated plasma proteomic…
By newseditor
Posted 27 Mar
APP antisense oligonucleoti…
By newseditor
Posted 27 Mar
Targeting Erbin-mitochondri…
By newseditor
Posted 27 Mar
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar