Biochemistry of Alzheimer's disease

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.^[1] 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.^[2] The presenilins are components of proteolytic complex involved in APP processing and degradation.^[3][4]

Amyloid beta monomers are soluble and contain short regions of beta sheet and polyproline II helix secondary structures in solution,^[5] though they are largely alpha helical in membranes;^[6] 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.^[7] 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.^[8][9]

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^[10] 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.^[11][12]

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.^[13][14] 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.^[15] Much of the known biochemistry of Alzheimer's disease has been deciphered through research using experimental models of Alzheimer's disease.