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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Biochemistry of Alzheimer's disease | 4/5 | https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer's_disease | reference | science, encyclopedia | 2026-05-05T11:04:17.929946+00:00 | kb-cron |
=== Oxidative stress === Oxidative stress is emerging as a key factor in the pathogenesis of AD. Reactive oxygen species (ROS) over-production is thought to play a critical role in the accumulation and deposition of amyloid beta in AD. Brains of AD patients have elevated levels of oxidative DNA damage in both nuclear and mitochondrial DNA, but the mitochondrial DNA has approximately 10-fold higher levels than nuclear DNA. Aged mitochondria may be the critical factor in the origin of neurodegeneration in AD. Even individuals with mild cognitive impairment, the phase between normal aging and early dementia, have increased oxidative damage in their nuclear and mitochondrial brain DNA (see Aging brain). Naturally occurring DNA double-strand breaks (DSBs) arise in human cells largely from single-strand breaks induced by various processes including the activity of reactive oxygen species, topoisomerases, and hydrolysis due to thermal fluctuations. In neurons DSBs are induced by a type II topoisomerase as part of the physiologic process of memory formation. DSBs are present in both neurons and astrocytes in the postmortem human hippocampus of AD patients at a higher level than in non-AD individuals. AD is associated with an accumulation of DSBs in neurons and astrocytes in the hippocampus and frontal cortex from early stages onward. DSBs are increased in the vicinity of amyloid plaques in the hippocampus, indicating a potential role for Aβ in DSB accumulation or vice versa. The predominant mechanism for repairing DNA double-strand breaks is non-homologous end joining (NHEJ), a mechanism that utilizes the DNA-dependent protein kinase (DNA-PK) complex. The end joining activity and protein levels of DNA-PK catalytic subunit are significantly lower in AD brains than in normal brains.
=== Cholesterol hypothesis === The cholesterol hypothesis is a combination of the amyloid hypothesis, tau hypothesis, and potentially the inflammatory hypothesis. Cholesterol was shown to be upstream of both amyloid and tau production. The cholesterol is produced in the astrocytes and shipped to neurons where it activates amyloid production through a process called substrate presentation. The process required apoE. Cholesterol's regulation of Tau production is less well understood, but knocking out the cholesterol synthesis enzyme SREBP2 decreased Tau phosphorylation. Innate immunity triggers cholesterol synthesis and cells take up the cholesterol. Presumably a cell in the brain dies with old age and this triggers innate immunity. More studies are needed to directly tie the inflammatory hypothesis to cholesterol synthesis in the brain.
=== Lipid invasion hypothesis === The Lipid Invasion Model (LIM) is a hypothesis for AD published in 2022, which argues that AD is a result of external lipid invasion to the brain, following damage to the blood-brain barrier (BBB). The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD (including old age, ApoE4, Aβ, brain trauma, high blood pressure, smoking, type 2 diabetes, obesity, alcohol, stress and sleep deprivation), most of which are also associated with damage to the BBB. The LIM can be viewed as a development of the cholesterol hypothesis, and incorporates and extends the amyloid hypothesis, the current dominant explanation of the disease. It goes back a step to argue that the cause of the amyloid plaques, neurofibrillary/tau tangles and many other features of the disease is the invasion of Low-density lipoprotein (LDL) and other forms of 'bad cholesterol' along with free fatty acids (FFAs) into the brain, following breakdown of the BBB. Such lipids would normally be excluded from the brain by the BBB. The LIM argues that the influx of 'bad cholesterol' is the primary cause of the excess Aβ, plaque formation and neurofibrillary/tau tangles in Late Onset AD (LOAD), due to changes in lipid raft composition and endosomal-lysosomal trafficking. This concurs with a large body of evidence showing an association of excess cholesterol with increased Aβ production, amyloid plaques and neurofibrillary/tau tangles. Plaques and tangles are thought to contribute to memory loss in AD. However, not all AD brains display plaques or tangles, and plaques and tangles do not always lead to AD. Therefore, the LIM proposes that it is the FFAs, rather than cholesterol-driven Aβ, that could be the primary drivers of AD. FFAs can account for all the common features of AD, including amnesia, synaptic disruption, neuroinflammation, brain shrinkage, body clock disruption, changes in brain energy production from glucose to ketone bodies, mitochondrial toxicity and oxidative stress within neurons. The LIM argues that the impact of the FFAs could cause most of the memory loss in AD, in addition to the spatial confusion, sleep disruption and sometimes paranoia also associated with the disease. The Lipid Invasion Model is the only model of AD that explains both the plaques and neurofibrillary/tau tangles commonly seen in LOAD (which accounts for 95% of AD cases), as well as all the other standard features of AD. It also explains why AD so disproportionally affects older people, and the high instance in contact sports players. By arguing that the root cause of AD is primarily damage to the BBB and the subsequent invasion of harmful lipids, the model offers new insights into the fundamental causes of AD, and potential new pathways for remedies for the disease. The LIM may also provide insights into other dementias and neurological diseases, such as Parkinson's and ALS/Motor Neurone Disease.