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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Biochemistry of Alzheimer's disease | 2/5 | https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer's_disease | reference | science, encyclopedia | 2026-05-05T11:04:17.929946+00:00 | kb-cron |
== Disease mechanisms == While the gross histological features of AD in the brain have been well characterized, several different hypotheses have been advanced regarding the primary cause. Among the oldest hypotheses is the cholinergic hypothesis, which suggests that deficiency in cholinergic signaling initiates the progression of the disease. Current theories establish that both misfolding tau protein inside the cell and aggregation of amyloid beta outside the cell initiates the cascade leading to AD pathology. Newer potential hypotheses propose metabolic factors, vascular disturbance, lipid invasion and chronically elevated inflammation in the brain as contributing factors to AD. The amyloid beta hypothesis of molecular initiation have become dominant among many researchers to date. The amyloid and tau hypothesis are the most widely accepted.
=== Tau hypothesis === The hypothesis that tau is the primary causative factor has long been grounded in the observation that deposition of amyloid plaques does not correlate well with neuron loss. A mechanism for neurotoxicity has been proposed based on the loss of microtubule-stabilizing tau protein that leads to the degradation of the cytoskeleton. However, consensus has not been reached on whether tau hyperphosphorylation precedes or is caused by the formation of the abnormal helical filament aggregates. Support for the tau hypothesis also derives from the existence of other diseases known as tauopathies in which the same protein is identifiably misfolded. However, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.
=== Amyloid hypothesis === The amyloid hypothesis was proposed because the gene for the amyloid beta precursor APP is located on chromosome 21, and patients with trisomy 21 – better known as Down syndrome – who have an extra gene copy exhibit AD-like disorders by 40 years of age. The amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing apoptosis. This hypothesis is supported by the observation that higher levels of a variant of the beta amyloid protein known to form fibrils faster in vitro correlate with earlier onset and greater cognitive impairment in mouse models and with AD diagnosis in humans. However, mechanisms for the induced calcium influx, or proposals for alternative cytotoxic mechanisms, by mature fibrils are not obvious.
A more recent variation of the amyloid hypothesis identifies the cytotoxic species as an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species, possibly toroidal or star-shaped with a central channel that may induce apoptosis by physically piercing the cell membrane. This ion channel hypothesis postulates that oligomers of soluble, non-fibrillar Aβ form membrane ion channels allowing unregulated calcium influx into neurons. A related alternative suggests that a globular oligomer localized to dendritic processes and axons in neurons is the cytotoxic species. The prefibrillar aggregates were shown to be able to disrupt the membrane. The cytotoxic-fibril hypothesis presents a clear target for drug development: inhibit the fibrillization process. Much early development work on lead compounds has focused on this inhibition; most are also reported to reduce neurotoxicity, but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta. For example, apomorphine was seen to significantly improve memory function through the increased successful completion of the Morris Water Maze.
Soluble intracellular (o)Aβ42 Two papers have shown that oligomeric (o)Aβ42 (a species of Aβ), in soluble intracellular form, acutely inhibits synaptic transmission, a pathophysiology that characterizes AD (in its early stages), by activating casein kinase 2.
=== Inflammatory hypothesis === Converging evidence suggests that a sustained inflammatory response in the brain is a core modifying feature of AD pathology and may be a key modifying factor in AD pathogenesis. The brains of AD patients exhibit several markers of increased inflammatory signaling. The inflammatory hypothesis proposes that chronically elevated inflammation in the brain is a crucial component to the amyloid cascade in the early phases of AD and magnifies disease severity in later stages of AD. Aβ is present in healthy brains and serves a vital physiological function in recovery from neuronal injury, protection from infection, and repair of the blood-brain barrier, however it is unknown how Aβ production starts to exceed the clearance capacity of the brain and initiates AD progression. A possible explanation is that Aβ causes microglia, the resident immune cell of the brain, to become activated and secrete pro-inflammatory signaling molecules, called cytokines, which recruit other local microglia. While acute microglial activation, as in response to injury, is beneficial and allows microglia to clear Aβ and other cellular debris via phagocytosis, chronically activated microglia exhibit decreased efficiency in Aβ clearance. Despite this reduced AB clearance capacity, activated microglia continue to secrete pro-inflammatory cytokines like interleukins 1β and 6 (IL-6, IL-1β) and tumor necrosis factor-alpha (TNF-a), as well as reactive oxygen species which disrupt healthy synaptic functioning and eventually cause neuronal death. The loss of synaptic functioning and later neuronal death is responsible for the cognitive impairments and loss of volume in key brain regions which are associated with AD. IL-1B, IL-6, and TNF-a cause further production of Aβ oligomers, as well as tau hyperphosphorylation, leading to continued microglia activation and creating a feed forward mechanism in which Aβ production is increased and Aβ clearance is decreased eventually causing the formation of Aβ plaques.