Biochemistry of Alzheimer's disease

The biochemistry of Alzheimer's disease (AD), one of the most common causes of adult dementia, is not yet very well understood. AD has been identified as a possible protein misfolding disease due to the accumulation of abnormally folded amyloid beta protein in the brains of Alzheimer's patients. Amyloid beta, also written Aβ, is a short peptide that is an abnormal 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 proteolytic complex involved in APP processing and degradation. The biochemistry of Alzheimer's disease (AD), one of the most common causes of adult dementia, is not yet very well understood. AD has been identified as a possible protein misfolding disease due to the accumulation of abnormally folded amyloid beta protein in the brains of Alzheimer's patients. Amyloid beta, also written Aβ, is a short peptide that is an abnormal 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 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 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. Although little is known about the process of filament assembly, it has recently been shown that a depletion of a prolyl isomerase protein in the parvulin family accelerates 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. 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. Fundamental to the understanding of Alzheimer's disease is the biochemical events that leads to accumulation of the amyloid-beta and tau-protein. A delicate balance of the enzymes secretases regulate the amyloid-beta accumulation. Alpha secretase activity discourages its 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 like prion diseases. 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.