Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease

The article in 3 sentences.

  1. Aside from the amyloid cascade hypothesis, the mitochondrial cascade hypothesis is another prominent thesis for the cause of Alzheimer’s disease. Interestingly, there are two schools of thought on the mitochondria’s contribution: (1) mitochondrial dysfunction induces pathological hallmarks of AD including Abeta and P-tau; (2) mitochondrial dysfunction is an intermediate step majority initiated by Abeta deposition.
  2. The mitochondrial cascade hypothesis is based on the premise that mitochondrial dysfunction impairs energy production, induces oxidative stress, damages mitochondrial DNA, dysregulates calcium signalling, alters mitochondrial motility, disturbs mitophagy, and leads to mitochondrial membrane permeabilization and apoptosis.
  3. The disruption of neurotransmission, a hallmark and a therapeutic target in Alzheimer’s disease, appears to interact with the mitochondrial dysfunction as a cause and consequence of each other, resulting in a vicious cycle towards neuronal death.

AChE, which breakdowns down synaptic acetylcholine, is enhanced by oxidative stress from mitochondrial dysfunction. The enhanced AChE activity produces higher ROS levels which damage mitochondria, forming a vicious cycle of lowered ACh levels in the synapse.

How has the article changed my thinking?

  1. Never did I know that there existed another pathogenic cascade leading to Alzheimer’s disease other than the amyloid cascade hypothesis. Now I know that the puzzle may be far more complicated and certainly involves the mitochondria and neurotransmitters as key players.
  2. The mitochondria and neurotransmitter hypothesis certainly encompasses the full spectrum of clinical presentation in Alzheimer’s disease—from cognitive impairment to neuropsychiatric symptoms–given the fundamental and widespread impact of a breakdown of this powerhouse. This is as opposed to the notion that Alzheimer’s disease, as herald by Abeta, is merely a disease of memory.
  3. Treating Alzheimer’s disease is a daunting task to achieve by targeting a single point of defect, as it is with the case of a gene therapy strategies targeting the DNA level. Perhaps other treatment modalities targeting further downstream, broad-based processes would be a more logical way forward.

What are some related / contradicting ideas?

Further reading:

  1. Ff Silva D, R Esteves A, R Oliveira C, M Cardoso S 28. Mitochondria: the common upstream driver of amyloid-β and tau pathology in Alzheimer’s disease. Current Alzheimer Research, 8:563-572.
  2. Swerdlow RH, Khan SM (2004). A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Medical hypotheses, 63:8-20.
  3. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, et al. (2001). Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci, 21:3017-3023.
  4. Beal MF, Hyman BT, Koroshetz W (1993). Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends in neurosciences, 16:125-131.
  5. Oliver DMA, Reddy PH (2019). Molecular Basis of Alzheimer’s Disease: Focus on Mitochondria. J Alzheimers Dis:1-22.
  6. Swerdlow RH (2018). Mitochondria and Mitochondrial Cascades in Alzheimer’s Disease. J Alzheimers Dis, 62:1403-1416.

References:

  • Author: Kan Yin Wong, Lee Wei Lim
  • Original text: click here