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Exploring the pathogenesis of Alzheimer's disease

In the exploration of pathogenesis of Alzheimer's disease, many studies have revealed the origin of the disease and the underlying cause of its deterioration. For a long time, we have known that pathological changes in the brain of patients with Alzheimer's disease, such as the accumulation of amyloid plaques, occurred before the onset of symptoms such as memory loss.

A new study published in Communications Biology by neuroscientists from the Massachusetts Institute of Technology provided new insights into the accumulation mechanism of the amyloid plate in the mouse brain. The study showed that the degree of amyloid accumulation in the relevant regions of the human brain is closely related to the worsening of the disease. Using a brain labeling technique called "SWITCH", the researchers fine-tuned the brains of mice at different ages and found that plaques first appeared in deep brain structures such as the papillae, lateral septum and hypothalamus areas of equal depth in the brain, then spread along specific brain circuits within 6 to 12 months, and eventually enter the hippocampus (a key area of memory) and the cortex. In addition, according to a study published by the journal Cell, researchers from the Massachusetts Medical College found that genetic mutations trigger a mutation in a protein called "ataxin-1," which is likely to regulate the activity of beta-amylase and thus increase an individual's risk of developing Alzheimer's disease. 

In an article published in the journal "PNAS", researchers from Binghamton University and the University of Colorado have jointly drawn a structural map of "amyloid" aggregates. In this study, the authors used high-resolution solid-state nuclear magnetic resonance spectroscopy to study these fibrous structures. Their work revealed that these fibers may have mutated in the molecular structure of the human brain's amyloid deposits. This may be the cause of the disease. 

In a study published in the journal Science, researchers from the Technical University of Munich, Germany, found for the first time that the excitatory neurotransmitter glutamic acid persisted for too long near active neurons. This causes these neurons to suffer from pathological overstimulation, which is likely to be a key factor in the loss of learning and memory in patients with Alzheimer's disease. As we all know, neurons use chemicals called "neurotransmitters" to communicate with each other. As one of the most important chemicals, glutamic acid plays a role in activating adjacent neurons. Researchers have found that under the action of beta-amyloid molecules: glutamate is difficult to transport out of the synaptic space normally. Therefore, high concentrations of glutamic acid persist in the synaptic space of highly active neurons for too long, resulting in excessive stimulation intensity. They tested similar mechanisms using beta-amyloid molecules from patient samples and tested them with various mouse models, all with similar results.

In an article published in the journal Cell Reports, researchers at the University of California, San Diego (UCSD) School of Medicine used transcriptomics to compare information on 414 patients clinically diagnosed Alzheimer's. Finally, a map of gene-protein interactions was drawn. The authors believe that combining protein interactions with gene interference activities can provide a comprehensive framework for describing changes in related molecular networks during the onset of Alzheimer's disease. Similarly, another study was published in the journal Neuron. In this study, researchers from Massachusetts General Hospital revealed the mechanism of interaction between CD33, a key gene of patients' brain pro-inflammatory response, and the anti-inflammatory gene TREM2. It also emphasizes the role of the interaction between the two in the origin of Alzheimer's disease. In another study published in the journal Nature Communications, researchers at the Center for Brain Science at the Japan Institute of Physics and Chemistry revealed the role of a gene called CAPON in regulating the pathogenesis of amyloid plaques and tau protein.

A study published in the journal Nature Neuroscience established a link between Alzheimer's disease and cellular autophagy. In Alzheimer's as well as other dementias, the accumulation of proteins tau and β- amyloid in the brain is responsible for cell death. In a new animal model, researchers have shown that the rate of this accumulation process slows as mitochondrial autophagy activity increases. Another study, also published in the journal Nature Neuroscience, revealed the causes of cerebral ischemic symptoms in Alzheimer's patients. The authors found that the inflammatory response in patients' brains led to the accumulation of neutrophils, which in turn triggered the clogging of capillaries in the brain and eventually results in reduced blood flow and the appearance of ischemic symptoms. In a study published in the journal Science, researchers from the Washington University School of Medicine found that lack of sleep increases the level of tau, a key protein in Alzheimer's disease. In this study, the researchers inoculated tau protein clumps into the hippocampus of a group of mice and then kept those mice awake for a long time each day. Another group of mice also received tau tangle injections but was not forced to stay awake. After four weeks, the tau tangles spread farther in mice that lacked sleep compared to resting mice. These findings suggest that insufficient sleep helps to promote Alzheimer's, and good sleep habits may help keep your brain healthy.

In short, the pathogenesis of Alzheimer's disease has not been fully clarified, so the treatment is only symptomatic treatment, there are still many problems to be solved in this field.


  1. Rebecca Gail Canter,et al.,3D mapping reveals network-specific amyloid progression and subcortical susceptibility in mice. Communications Biology, 2019; 2 (1)
  2. Jaehong Suh,Donna M. Romano,Larissa Nitschke,et al., Loss of Ataxin-1 Potentiates Alzheimer’s Pathogenesis by Elevating Cerebral BACE1 Transcription, Cell (2019).
  3. Zhi-Wen Hu et al., Molecular structure of an N-terminal phosphorylated β-amyloid fibril, Proceedings of the National Academy of Sciences (2019).
  4. Benedikt Zott et al., A vicious cycle of β amyloid–dependent neuronal hyperactivation. Science, 2019.
  5. Saranya Canchi et al., Integrating Gene and Protein Expression Reveals Perturbed Functional Networks in Alzheimer's Disease Cell Reports (2019).
  6. Shoko Hashimoto et al., Tau binding protein CAPON induces tau aggregation and neurodegeneration, Nature Communications (2019).
  7. Evandro F. Fang et al., Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nature Neuroscience, 2019.
  8. Jean C. Cruz Hernández et al., Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer's disease mouse modelsHealth Fitness Articles, Nature Neuroscience (2019)

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