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| Biochemistry of Alzheimer's disease | 1/5 | https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer's_disease | reference | science, encyclopedia | 2026-05-05T11:04:17.929946+00:00 | kb-cron |
The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation. Amyloid beta monomers are soluble and contain short regions of beta sheet and polyproline II helix secondary structures in solution, though they are largely alpha helical in membranes; however, at sufficiently high concentration, they undergo a dramatic conformational change to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils. These fibrils and oligomeric forms of Aβ deposit outside neurons in formations known as senile plaques. There are different types of plaques, including the diffuse, compact, cored or neuritic plaque types, as well as Aβ deposits in the walls of small blood vessel walls in the brain called cerebral amyloid angiopathy. AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in Alzheimer's disease, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques. Although little is known about the process of filament assembly, depletion of a prolyl isomerase protein in the parvulin family has been shown to accelerate the accumulation of abnormal tau. Neuroinflammation is also involved in the complex cascade leading to AD pathology and symptoms. Considerable pathological and clinical evidence documents immunological changes associated with AD, including increased pro-inflammatory cytokine concentrations in the blood and cerebrospinal fluid. Whether these changes may be a cause or consequence of AD remains to be fully understood, but inflammation within the brain, including increased reactivity of the resident microglia towards amyloid deposits, has been implicated in the pathogenesis and progression of AD. Much of the known biochemistry of Alzheimer's disease has been deciphered through research using experimental models of Alzheimer's disease.
== Neuropathology == At a macroscopic level, AD is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains. Plaques are dense, mostly insoluble deposits of protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.
== Biochemical characteristics ==
Fundamental to the understanding of Alzheimer's disease is the biochemical events that leads to accumulation of the amyloid-beta plaques and tau-protein tangles. A delicate balance of the enzymes secretases regulate the amyloid-beta accumulation. Recently, a link between cholinergic neuronal activity and the activity of alpha-secretase has been highlighted, which can discourage amyloid-beta proteins deposition in brain of patients with Alzheimer's disease.
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded amyloid-beta proteins in the brains of AD patients. Abnormal amyloid-beta accumulation can first be detected using cerebrospinal fluid analysis and later using positron emission tomography (PET).
Although AD shares pathophysiological mechanisms with prion diseases, it is not transmissible in the wild, as prion diseases are. Any transmissibility that it may have is limited solely to extremely rare iatrogenic events from donor-derived therapies that are no longer used. Amyloid-beta, also written Aβ, is a short peptide that is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of a proteolytic complex involved in APP processing and degradation.
Although amyloid beta monomers are harmless, they undergo a dramatic conformational change at sufficiently high concentration to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils that deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques.
Levels of the neurotransmitter acetylcholine (ACh) are reduced. Levels of other neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Replenishing the ACh by anti-cholinesterases is an approved mode of treatment by FDA. An alternative method of stimulating ACh receptors of M1-M3 types by synthetic agonists that have a slower rate of dissociation from the receptor has been proposed as next generation cholinomimetic in Alzheimer's disease.