Alzheimer’s disease is very complex and incompletely understood because the brain is very complex and incompletely understood. Efforts to make progress towards therapies for Alzheimer’s disease have progressed in parallel with, and often driven and funded, efforts to map the works of the brain at the detail level of cellular biochemistry. Even though Alzheimer’s will turn out to have easily stated causes, a set of comparatively simple biochemical processes, even simple origins expand – over time and through chains of cause and effect – to produce end state conditions that are as complex as their environment.
Researchers tend to specialize. There is too much biochemistry to hold it all in one mind, even for a single medical condition. So the research community tends to act in practice much like the blind men and the elephant, everyone focused on their particular facet of the larger condition. Focus is necessary to make progress on understanding that facet, but at the end of the day someone needs to occasionally review all of the facets together to see if the picture still makes sense. Synthesis is an increasingly important function in modern life science research, becoming ever more challenging as the facets grow in size, but sadly undervalued. Alzheimer’s research and development still awaits a definitive synthesis, the theory and proof that will show us which of the facets of the condition are important, which are primary and which are secondary.
The open access paper here discusses the oxidative stress view of Alzheimer’s disease, a basis for considering progression of the condition that doesn’t get as much attention as work on aggregates of amyloid-β and tau. Oxidative stress refers to the rising level of oxidative molecules and signs of the damage they do to molecular machinery inside and outside cells. Oxidation is a fact of life in cells, a necessary part of the way in which biology works: damage happens constantly, and is repaired constantly. Ever more oxidative damage and oxidative molecules are present in the body and brain with the progression of aging, alongside a growth in chronic inflammation – oxidative stress and inflammation are usually found together, linked by a number of mechanisms. Alzheimer’s and most other neurodegenerative conditions appear to have a strong inflammatory component, and thus there is oxidative stress to observe as well.
Nowadays, Alzheimer’s disease (AD) is the most diagnosed type of dementia. For a long time, amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) have been considered unquestionably the main cause of AD pathogenesis, but many other theories have been proposed, including oxidative stress and neuroinflammation, to explain a still unknown disease.
For many years, the amyloid cascade hypothesis has dominated AD thinking, modeling, and therapeutic approach. Amyloid proteins are beta-sheet proteins that can easily aggregate. Aβ is a proteolytic degradation product of a larger molecule called amyloid-β protein precursor (AβPP). The amyloid cascade hypothesis postulates an overproduction of Aβ, which leads to neuronal dysfunction and apoptosis causing AD clinical manifestations. According to this hypothesis, amyloid accumulation represents the “upstream” event in AD pathogenesis. This point of view has been overcome by the possibility that soluble Aβ oligomers, more than mature amyloid plaques, are the key toxic moieties. In fact, it has been demonstrated that amyloid oligomers may access intracellular organelles, including mitochondria, and compromise their function. Amyloid deposition causes local inflammatory and immunologic alterations for a direct neurotoxicity with microglial recruitment and astrocyte activation. It is also associated with the release of cytokines, nitric oxide, and other radical species that can promote neuroinflammation and neurodegeneration.
In addition to the amyloid cascade, intracellular neurofibrillary tangles (NFTs) are found in AD brain. They consist of hyperphosphorylated tau protein. Interestingly, NFTs correlate more closely with the severity of dementia than plaque counts. The association of tangles with a variety of brain damage supports the “tauopathy” concept of neurodegeneration, although tauopathy as a primary cause of neurodegenerative diseases is currently demonstrable only in a subgroup of familial frontotemporal dementia. However, the recent failures of drugs targeting amyloid pathways have raised questions not only about this approach but also on the validity of the amyloid cascade hypothesis itself.
Oxidative stress is a condition where reactive oxygen species (ROS) production exceeds the cellular antioxidant defense system. The brain is highly susceptible to an oxidative imbalance due to its high-energy demand, high oxygen consumption, an abundance of easily peroxidable polyunsaturated fatty acids, high level of potent ROS catalyst iron, and a relative paucity of antioxidant enzymes, this latter more evident in AD brain. Mitochondria are prone to oxidative damage. Mitochondrial DNA (mtDNA) is particularly susceptible to oxidative damage. The simultaneous increased oxidation of mtDNA and deficiency of DNA repair could enhance the lesion to mitochondrial genome, potentially causing neuronal damages. On this basis, it is reasonable that oxidatively mediated damage to biomolecules is extensively reported in AD, suggesting that oxidative stress plays a critical role in the disease pathogenesis. As the main source of ROS generation and a major target of oxidative damage, progressive impairment of mitochondria has been implicated in aging and AD.
It is generally accepted that mitochondrial function progressively declines along with age when compensation is no longer possible. In summary, the mitochondrial cascade hypothesis proposes that every single person has a genetically determined mitochondrial starting line, that together with environmental factors determine the age at which clinical disease may ensue. Thus, the “mitochondrial cascade hypothesis” places the mitochondrial dysfunction as the leading factor in the late-onset AD pathology cascade, underlying the individual genetic background able to regulate since birth its mitochondrial function and sustainability. For this reason, the rate at which age-related mitochondrial dysfunction proceeds differs among individuals. When the mitochondrial function declines and falls below a critical threshold, AD-typical dysfunction at the cellular level may ensue, including Aβ production, tau phosphorylation, synaptic degeneration, and oxidative stress.