Amyloid plaques

Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease.

The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve, with an average plaque area of 400–450 square micrometers (μm²). The smallest plaques (less than 200 μm²), which often consist of diffuse deposits of Aβ, are particularly numerous. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid.

In 1892, Paul Blocq and Gheorghe Marinescu first described the presence of plaques in grey matter. They referred to the plaques as 'nodules of neuroglial sclerosis'. In 1898, Emil Redlich reported plaques in three patients, two of whom had clinically verified dementia. Redlich used the term 'miliary sclerosis' to describe plaques because he thought they resembled millet seeds, and he was the first to refer to the lesions as 'plaques'.

In the early 20th century, Oskar Fischer noted their similarity to actinomyces 'Drusen' (geode-like lesions), leading him to call the degenerative process 'drusige Nekrose'. Alois Alzheimer is often credited with first linking plaques to dementia in a 1906 presentation (published in 1907), but this short report focused mainly on neurofibrillary tangles, and plaques were only briefly mentioned. Alzheimer's first substantive description of plaques appeared in 1911. In contrast, Oskar Fischer published a series of comprehensive investigations of plaques and dementia in 1907, 1910 and 1912. By 1911, Max Bielschowsky proposed the amyloid-nature of plaque deposits. This was later confirmed by Paul Divry, who showed that plaques that are stained with the dye Congo Red show the optical property of birefringence, which is characteristic of amyloids in general.

In 1911, Teofil Simchowicz introduced the term 'senile plaques' to denote their frequent presence in the brains of older individuals. In 1968, a quantitative analysis confirmed the association of senile plaques with dementia. The term 'neuritic plaques' was used in 1973 to designate plaques that include abnormal neuronal processes (neurites). An advance in 1984 and 1985 was the identification of Aβ as the protein that forms the cores of plaques. This discovery led to the generation of new tools to study plaques, particularly antibodies to Aβ, and presented a molecular target for the development of potential therapies for Alzheimer's disease.

Amyloid beta (Aβ) is a small protein, most often 40 or 42 amino acids in length, that is released from a longer parent protein called the Aβ-precursor protein (APP). APP is produced by many types of cell in the body, but it is especially abundant in neurons. It is a single-pass transmembrane protein, passing once through cellular membranes.

The Aβ segment of APP is partly within the membrane and partly outside of the membrane. To liberate Aβ, APP is sequentially cleaved by two enzymes: first, by beta secretase (or β-amyloid cleaving enzyme (BACE)) outside the membrane, and second, by gamma secretase (γ-secretase), an enzyme complex within the membrane. The sequential actions of these secretases results in Aβ protein fragments that are released into the extracellular space. In addition to Aβ peptides that are 40 or 42 amino acids long, several less abundant Aβ fragments also are generated. Aβ can be chemically modified in various ways, and the length of the protein and chemical modifications can influence both its tendency to aggregate and its toxicity.

Amyloid plaques are visible with the light microscope using a variety of staining techniques, including silver stains, Congo red, Thioflavin, cresyl violet, PAS-reaction, and luminescent conjugated oligothiophenes (LCOs). These methods often stain different components of the plaques, and they vary in their sensitivity Plaques may also be visualized immunohistochemically with antibodies directed against Aβ or other components of the lesions. Immunohistochemical stains are especially useful because they are both sensitive and specific for antigens that are associated with plaques.