Role of oxidative stress in Alzheimer’s disease

-In Alzheimer’s, oxidative stress slowly frays the brain’s wiring, dimming the sparks of memory and thought.

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Introduction:

Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic, with age representing the greatest risk factor. 

The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases, including AD. 

AD is caused by the involvement of various genetic, environmental, and lifestyle factors that affect neuronal cells to degenerate over time. Oxidative stress is engaged in the pathogenesis of various disorders, and its key role is also linked to the etiology of AD. AD is attributed to neuronal loss, abnormal accumulation of Amyloid-β (Aβ), and neurofibrillary tangles (NFTs) with severe memory impairments and other cognitive dysfunctions, which lead to the loss of synapses and neuronal death and eventual demise of the individual. Increased production of reactive oxygen species (ROS), loss of mitochondrial function, altered metal homeostasis, aberrant accumulation of senile plaque, and mitigated antioxidant defense mechanisms are all involved in the progression of AD. In spite of recent advances in biomedical research, the underlying mechanism of disruption of redox balance and the actual source of oxidative stress are still obscure.

Causes and effects of oxidative stress.

Oxidative stress and Abeta-induced toxicity

In the brain, there’s a building block protein called APP. Most of the time, APP gets recycled harmlessly, and the city keeps running smoothly.

But sometimes, APP is cut by the “wrong scissors,”  two enzymes called beta-secretase and gamma-secretase. When this happens, they snip out a fragment known as amyloid-beta (Aβ).

Here’s the problem: one form of Aβ, called Aβ42, is like sticky chewing gum. It clumps together quickly, forming tiny clusters (oligomers) that jam the communication lines between brain cells. These jams weaken the power grid, leading to memory problems, confusion, and eventually the breakdown we see in Alzheimer’s disease.

There is a safer pair of scissors, though, alpha-secretase. When APP is cut this way, no toxic Aβ is made, and the city stays peaceful.

But when production of Aβ goes up, or the brain struggles to clear it out, those sticky clumps pile up, sparking the chain reaction that damages neurons and fuels Alzheimer’s

Mitochondrial dysfunction and oxidative stress in AD

Mitochondria are often called the powerhouses of the cell because they make energy (ATP), regulate calcium levels, and even decide whether a cell survives or dies. But in Alzheimer’s disease, these tiny organelles don’t work as they should.

Mitochondria are also the main place where reactive oxygen species (ROS), harmful molecules that cause oxidative stress, are produced. Since they’re directly exposed to ROS, mitochondria are especially vulnerable to damage.

Studies on Alzheimer’s brains have shown:

• Fewer healthy mitochondria in neurons, especially in the memory-critical hippocampus.

• Damaged mitochondrial DNA and proteins are piling up inside cells.

• Signs of oxidative stress, with chemical markers of damage appearing in brain tissue.

• Reduced activity of cytochrome oxidase (complex IV), a key enzyme in the energy-making chain.

When mitochondria can’t keep up, the result is less energy, more oxidative stress, and ultimately, greater damage to neurons fueling the progression of Alzheimer’s disease.

Conclusion:

In summary, evidence has demonstrated that oxidative stress is inextricably linked with several major pathological processes in AD, including Abeta-induced neurotoxicity, mitochondrial dysfunction. Excessive ROS may be generated from mitochondrial dysfunction and/or aberrant accumulation of transition metals, perhaps caused by a combination of abnormal Abeta accumulation, eventually resulting in oxidative stress.

References:

1 Querfurth H. W. and LaFerla F. M., Alzheimer′s disease, The New England Journal of Medicine. (2010) 362, no. 4, 329–344, 2-s2.0-75449102536, https://doi.org/10.1056/NEJMra0909142.

2 2010 Alzheimer′s disease facts and figures, Alzheimer′s & Dementia. (2010) 

3.Praticò D., Oxidative stress hypothesis in Alzheimer′s disease: a reappraisal, Trends in Pharmacological Sciences. (2008) 29, no. 12, 609–615, 2-s2.0-56349145099, https://doi.org/10.1016/j.tips.2008.09.001.