Amyloid plaques

In 1892, Paul Blocq and Gheorghe Marinescu first described the presence of plaques in grey matter.[9][10] 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.[11] 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'.[4] 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'.[12] Alois Alzheimer is often credited with first linking plaques to dementia in a 1906 presentation (published in 1907),[13] but this short report focused mainly on neurofibrillary tangles, and plaques were only briefly mentioned.[4] Alzheimer's first substantive description of plaques appeared in 1911.[12] In contrast, Oskar Fischer published a series of comprehensive investigations of plaques and dementia in 1907, 1910 and 1912.[12] 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,[14] which is characteristic of amyloids in general.[15] In 1911, Teofil Simchowicz introduced the term 'senile plaques' to denote their frequent presence in the brains of older individuals.[16][17][18] In 1968, a quantitative analysis by Gary Blessed, Bernard Tomlinson and Martin Roth confirmed the association of senile plaques with dementia.[19] Henryk Wisniewski and Robert Terry coined the term 'neuritic plaques' in 1973 to designate plaques that include abnormal neuronal processes (neurites).[20] An important advance in 1984 and 1985 was the identification of Aβ as the protein that forms the cores of plaques.[21][22][23] 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.[4] Knowledge of the amino acid sequence of Aβ also enabled scientists to discover genetic mutations that cause autosomal dominant Alzheimer's disease, all of which increase the likelihood that Aβ will aggregate in the brain.[24][25][26]

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).[27] 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, that is, it passes once through cellular membranes.[28] 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.[28] The sequential actions of these secretases results in Aβ protein fragments that are released into the extracellular space[29][28] The discharge of Aβ is increased by the activity of synapses.[25] In addition to Aβ peptides that are 40 or 42 amino acids long, several less abundant Aβ fragments also are generated.[30][31] 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.[4]

Two amyloid plaques from the brain of a patient with Alzheimer's disease. In this photomicrograph, neurites are darkly stained with the Naoumenko-Feigin silver method, and the pink elements (including the plaque cores) are stained with the periodic acid-Schiff (PAS) counterstain. The bar is 20 microns (0.02 mm) in length.

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).[32][4][33] These methods often stain different components of the plaques, and they vary in their sensitivity[4][34] 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.

The Aβ deposits that comprise amyloid plaques are variable in size and appearance.[3][4] Under the light microscope, they range from small, wispy accumulations that are a few microns in diameter to much larger dense or diffuse masses. So-called 'classical plaques' consist of a compact Aβ-amyloid core that is surrounded by a corona of somewhat less densely packed Aβ.[4] Classical plaques also include abnormal, swollen neuronal processes (neurites) deriving from many different types of neurons, along with activated astrocytes and microglia.[3][4] Abnormal neurites and activated glial cells are not typical of most diffuse plaques, and it has been suggested that diffuse deposits are an early stage in the development of plaques.[35]

Dietmar Thal and his colleagues have proposed a sequence of stages of plaque formation in the brains of Alzheimer patients[36][37] In Phase 1, plaques appear in the neocortex; in Phase 2, they appear in the allocortex, hippocampal formation and amygdala; in Phase 3, the basal ganglia and diencephalon are affected; in Phase 4, plaques appear in the midbrain and medulla oblongata; and in Phase 5, they appear in the pons and cerebellum. Thus, in end-stage Alzheimer's disease, plaques can be found in most parts of the brain. They are uncommon in the spinal cord.[4]

The normal function of Aβ is not certain, but plaques arise when the protein misfolds and begins to accumulate in the brain by a process of molecular templating ('seeding').[38] Mathias Jucker and Lary Walker have likened this process to the formation and spread of prions in diseases known as spongiform encephalopathies or prion diseases.[38][39] According to the prion paradigm, certain proteins misfold into shapes that are rich in beta-sheet secondary structure. In this state, they cause other proteins of the same type to adopt the same abnormal beta-sheet-rich structure.[40] The misfolded proteins stick to one another, eventually stacking together to form oligomers that merge to make the amyloid fibrils that are typical of mature plaques.[7][41]

Abundant Aβ plaques, along with neurofibrillary tangles consisting of aggregated tau protein, are the two lesions that are required for the neuropathological diagnosis of Alzheimer's disease.[25][42] Although the number of neurofibrillary tangles correlates more strongly with the degree of dementia than does the number of plaques, genetic and pathologic findings indicate that Aβ plays a central role in the risk, onset, and progression of Alzheimer's disease.[24] Of particular importance is the longer (42 amino acids) species of Aβ known as Aβ42. Elevated levels of Aβ, as well as an increase in the ratio of Aβ42 to the 40-amino acid form (Aβ40), are important early events in the pathogenesis of Alzheimer's disease.[43]

Until recently, the diagnosis of Alzheimer's disease required a microscopic analysis of plaques and tangles in brain tissue, usually at autopsy.[44] However, Aβ plaques (along with cerebral Aβ-amyloid angiopathy) can now be detected in the brains of living subjects. This is done by preparing radiolabeled agents that bind selectively to Aβ deposits in the brain after being infused into the bloodstream.[45] The ligands cross the blood-brain barrier and attach to aggregated Aβ, and their retention in the brain is assessed by positron emission tomography (PET). In addition, the presence of plaques and tangles can be estimated by measuring the amounts of the Aβ and tau proteins in the cerebrospinal fluid.[46][47]

The probability of having plaques in the brain increases with advancing age.[48] From the age of 60 years (10%) to the age of 80 years (60%), the proportion of people with senile plaques increases linearly. Women are slightly more likely to have plaques than are men.[49][48] Both plaques and Alzheimer's disease also are more common in aging persons with trisomy-21 (Down syndrome).[1][50] This is thought to result from the excess production of Aβ because the APP gene is on chromosome 21, which exists as three copies in Down syndrome.[50]

Amyloid plaques naturally occur in the aging brains of nonhuman species ranging from birds to great apes.[4] In nonhuman primates, which are the closest biological relatives of humans, plaques have been found in all species examined thus far.[51] Neurofibrillary tangles are rare, however, and no nonhuman species has been shown to have dementia along with the complete neuropathology of Alzheimer's disease.[52]

Research has been directed toward understanding the biochemical, cytological, and inflammatory characteristics of plaques, determining how plaques arise and proliferate in the brain, identifying genetic and environmental risk factors, discovering methods to detect them in the living brain, and developing therapeutic strategies for preventing or removing them.[4] Research on the formation and proliferation of amyloid plaques has been accelerated by the development of genetically modified mouse models.[53][54] Despite some limitations, these models have also contributed to the discovery of new therapeutic strategies. For example, a growing variety of treatments that reduce Aβ levels and the number of plaques in the brain have been identified with the help of transgenic rodent models. These strategies include immunotherapeutic approaches and inhibitors of the secretases that release Aβ from APP.[25] Such treatments are now being clinically evaluated for the treatment of Alzheimer's disease.[43][25] The findings so far indicate that the removal of plaques in patients with dementia is of little benefit, possibly because the brain is severely damaged by the time the signs and symptoms of Alzheimer's disease first appear.[25][24] Microglia-mediated plaque formation may in fact be beneficial by encapsuling Aβ in dense plaque cores.[55][7] Mutations to a microglial receptor, TREM2, have been found to reduce the microglial response to plaques, and the plaques appear to take on a more toxic state.[56] Many researchers believe that earlier inhibition of Aβ aggregation and plaque formation is needed to slow or prevent tauopathy and the dementia of Alzheimer's disease. Other research is directed toward understanding the inflammation that is often associated with plaques[57] or identifying environmental, physiological and genetic risk factors for plaque formation and Alzheimer's disease.[58][59]

• Proteopathy

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• Cruz L, Urbanc B, Buldyrev SV, et al. (July 1997). "Aggregation and disaggregation of senile plaques in Alzheimer disease". Proceedings of the National Academy of Sciences of the United States of America. 94 (14): 7612–6. Bibcode:1997PNAS...94.7612C. doi:10.1073/pnas.94.14.7612. PMC 23870. PMID 9207140.