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Norman Fenton Group

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Karen Novikov
Karen Novikov

Amyloid Protein Plaque

Scientists can also see the terrible effects of Alzheimer's disease when they look at brain tissue under the microscope. Scientists are not absolutely sure what causes cell death and tissue loss in the Alzheimer's brain, but the plaques and tangles in the figures below are prime suspects.

amyloid protein plaque

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Plaques form when protein pieces called beta-amyloid (BAY-tuh AM-uh-loyd) clump together. Beta-amyloid comes from a larger protein found in the fatty membrane surrounding nerve cells.

The most damaging form of beta-amyloid may be groups of a few pieces rather than the plaques themselves. The small clumps may block cell-to-cell signaling at synapses. They may also activate immune system cells that trigger inflammation and devour disabled cells.

In mild to moderate stages, brain regions important in memory and thinking and planning develop more plaques and tangles than were present in early stages. As a result, individuals develop problems with memory or thinking serious enough to interfere with work or social life. They may also get confused and have trouble handling money, expressing themselves and organizing their thoughts. Many people with Alzheimer's are first diagnosed in these stages.

Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human amyloid protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of amyloidogenic Abeta peptides. The platelet-derived growth factor beta chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Abeta(1-42) levels, whereas an experimental mutation of the beta-secretase cleavage site (671(M-->I)) eliminated production of human Abeta. High levels of Abeta(1-42) resulted in age-dependent formation of amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with Abeta levels but not with hAPP levels or plaque load. We conclude that Abeta is synaptotoxic even in the absence of plaques and that high levels of Abeta(1-42) are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent Abeta toxicity plays an important role in the development of synaptic deficits in AD and related conditions.

Amyloid plaques are aggregates of misfolded proteins that form in the spaces between nerve cells. These abnormally configured proteins are thought to play a central role in Alzheimer's disease. The amyloid plaques first develop in the areas of the brain concerned with memory and other cognitive functions.

How beta-amyloid causes toxic damage to nerve cells is not quite clear, but some research suggests that it may split into fragments and release free radicals, which then attack neurons. Another theory is that the beta-amyloid forms tiny holes in neuronal membranes, which leads to an unregulated influx of calcium that can cause neuronal death. Regardless of the exact pathological process through which beta-amyloid causes neuronal damage, the result is that neurons die.

Plaques then form that are made up of a mixture of these degenerating neurons and the beta-amyloid aggregates. These plaques cannot be broken down and removed by the body, so they gradually accumulate in the brain. The accumulation of this amyloid leads to amyloidosis, which is thought to contribute to a number of neurodegenerative diseases.

This question has been the focus of drug development for many years. BrightFocus has funded the work of scientists who have shown various methods of clearing away plaques. For example, Dr. Matthew Campbell (Trinity College) has experimented with temporarily disrupting the blood-brain barrier to clear out existing plaques. After many heartbreaking clinical trial failures, there is growing concern among the scientific and medical communities that clearing plaques may not be sufficient to treat the disease. This is a very active area of research.

Neurofibrillary tangles are insoluble twisted fibers found inside the brain's cells. These tangles consist primarily of a protein called tau, which forms part of a structure called a microtubule. The microtubule helps transport nutrients and other important substances from one part of the nerve cell to another. In Alzheimer's disease, however, the tau protein is abnormal and the microtubule structures collapse.

The presence of plaques around a neuron causes them to die, possibly by triggering an immune response in the immediate area. Tangles form inside of neurons and interfere with the cellular machinery used to create and recycle proteins, which ultimately kills the cell.

This is not known. Proper diet and regular exercise are known to limit the formation of plaques and tangles. For more, visit other resources available on this site or the National Institutes of Health.

Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain.[1][2][3][4] 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.[5] Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles.[3] 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 (µm). The smallest plaques (less than 200 µm), which often consist of diffuse deposits of Aβ,[4] are particularly numerous.[6] The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope.[4] Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid.[7] Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state.[8]

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, passing 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] 041b061a72


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