The Effects Of Aβ Aggregates

The damage then alters the permeability of the axon membrane resulting in a large inflow of calcium, and the release of apoptotic cell death mediators that may be responsible for the phosphorylation, shortening, misfolding and aggregation of tau proteins (2011). Thus, the neurodegeneration that begins in the cortical sulci and initially surrounding only small blood vessels, spreads to larger portions of the brain. This tau-toxic factor associated systemic degeneration in regions of the brain that regulate emotion, memory, and other cognitive functions, leads to the physical and neuropsychological sequelae of CTE (McKee, et al., 2010).

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most widespread age-related neurodegenerative diseases. Both diseases impact a considerable number of people, where AD occurs in around 10 percent of the population greater than the age of 65 while PD occurs in roughly 1 percent of the population above the age of 65. AD is considered to be the most widespread cause of dementia, characterised by the progressive memory and cognitive deficits which impair ones day to day activities. The pathological hallmark of AD comprises of extracellular accumulation of senile plaques consisting of mainly amyloid-beta (Aβ) peptides, along with neurofibrillary tangles which are composed of the phosphorylated tau protein, located in the hippocampus and cortex. Conversely, PD is considered to be the most widespread movement disorder that is characterised by symptoms such as rigidity slow movements, resting tremor and other instabilities. The extreme loss of dopaminergic neurones in the substantia nigra is what defines PD, as the loss of this nerve cell can be linked to Lewy bodies containing aggregates of a soluble protein called α-synuclein.

Main reason for cognition decline could be buildup of plaque and dysfunctional proteins in the brain interfering with neuronal function. Alzheimer’s disease (AD) is an age-related neurodegenerative disease that accounts for more than 60 % of all dementia cases. The disease is characterized by cognitive deficits and memory loss through a process that lead to the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). This plaque is composed of abnormally hyperphosphorylated tau protein in the brain. Amyloid beta (Aβ or Abeta) is a peptide of 36–43 amino acids, forms amyloid plaques in the brain and are toxic to nerve cells. These peptides result from the amyloid precursor protein (APP), which is cleaved

Alzheimer’s disease, also known as AD is often insidious on set, it can take months up to years to go from a mild to severe impairment. (Mayeux, 2010) The disease is irreversible and has no cure. “The disease affects 500,000 Canadians, 71,000 of those are under the age of 65” (VanDenBroek, 2013). AD affects the person by impacting their neurological function, their cognition and their behaviour.

Alzheimer’s disease (AD) is a neurodegenerative disorder involving senile plaques distributed throughout the cerebral cortex and intracellular neurofibrillary tangles. These plaques are predominantly composed of beta-amyloid (Aβ), which is a 39 to 42 amino acid peptide and is cleaved from the (APP). With 1 in every 14 people over the age of

The two main biomarkers of AD are beta-amyloid (Aβ) and tau and are highly debated in regards to their function in AD pathophysiology. The production of beta-amyloid plaques may be due to improper functioning of the proteasome preventing the breakdown of Aβ. Support for this theory comes from research indicating that the 20S proteasome is responsible for Aβ degradation and that alterations to the kinetics of the proteasome increased Aβ levels (Zhao & Yang, 2010). These accumulated levels of Aβ plaques leads to lower levels of soluble Aβ, which is needed for memory formation. This may occur through activation of nicotinic acetylcholine (ACh) receptors and AChE levels are drastically reduced in AD patients. (Garcia-Osta & Alberini, 2009). The microtubule stabilizing protein tau may become hyper-phosphorylated in AD due to the presence of high levels of Aβ. Hoshi et al (1996) showed that Aβ exposure to rat hippocampal neurons in vitro produced increased levels of the tau kinase GSK-3 (glycogen synthase kinase 3) which in turn hyper-phosphorylated tau leading to cellular death. (Hoshi et al., 1996) The neurotoxicity of tau may not be produced solely because of GSK-3, but may be due to

β-amyloid aggregation spread from the site of injection to include both hemispheres of the brain further displaying the potentiation induced by aggregates within the brain homogenates (Stöhr et al, 2012). Under transmission electron microscopy, purified β-amyloid aggregates from transgenic mice revealed densely bundled fibrils; which were observed to increase levels of GFAP, Aβ(1-40) and Aβ(1-42) in bigenic mice at 300 days post injection via ELISA and immunoblotting (Stöhr et al, 2012). Crude brain homogenate exhibited approximately 15-20 times less β-amyloid than the purified homogenates (Stöhr et al, 2012). BLI of bigenic mouse brains injected with purified homogenate exhibited an early time of detection with signals at 161 + 7 [Tg(APP23)] and 173 + 9 [Tg(CRND8)] days (Stöhr et al, 2012). (FIGURE). Synthetic β-amyloid aggregates, wild-type Aβ(1-40) and mutant Aβ(AβS26C)2, were used to determine if prior results from purified brain homogenate could have contained any cofactors which would affect propagation of pathology (Stöhr et al, 2012). Results from the injection of synthetic fibrils into bigenic mice revealed similar β-amyloid aggregation, however pathology was less severe than purified brain homogenates from transgenic models (Stöhr et al, 2012). BLI of synthetic fibrils revealed a decrease in

There is a large supply of amyloid plaques in the cells of people with Alzheimer’s disease. Amyloid plaques are clustered pieces of protein that build up between nerve cells. They speed up the production of beta amyloid, which are polypeptides of about thirty-six to forty-three amino acids long (emedicinehealth, 2014; Stanford Medicine, 2013). Amyloid precursor proteins (APP), when split into specific pieces, are producers of beta amyloid. They are found in tissues and organs, such as the brain. Amyloid precursor proteins pass through a fatty membrane on the outside of a cell. This allows them to extend from the

APP’s protective role in TBI is currently understood to be the product of ɑ-secretase pathway in soluble amyloid precursor protein ɑ (sAPPɑ) (Corrigan et al. 2013). This pathway was discovered in the previous year by the same researchers who used APP knockout mice. The knockout mice had cognitive and motor functions that were severely compromised with impaired neuroreparative abilities compared to its wild-type counterpart (Corrigan et al. 2012). When the knockout mice were treated with sAPPɑ, however, their neuroreparative responses were restored.

Known as the fifth leading cause of death in the United States, Alzheimer’s disease (AD) affects approximately 5.3 million Americans and is the major cause of dementia. Although the cause of AD is unknown, the correlation between the damage caused by plaque in the brain and evidence of the disease suggests possible causality. Indicated by extracellular dense plaques and intracellular neurofibrillary tangles made of beta-amyloid and tau proteins, respectively, this neurodegenerative disease is thought to be a result of mutations in the amyloid precursor protein (APP), the genetic precursor of beta-amyloid peptides.

Alzheimer’s is described as a type of disease that causes mental illness, which causes problems with memory, thinking, and behavior of an individual. It is a deterioration of the nervous system especially the neurons in the brain. Alzheimers’ is the result of mutations on genes. Specifically, familial alzheimer’s is caused by a mutation in the gene coding for the amyloid precursor protein (APP) on chromosome 21q.When this gene is modified, a toxic protein fragment called amyloid beta peptide are produced in the brain. This peptide builds up in the brain and form amyloid plaques. The accumulation of this “amyloid beta peptide and amyloid plaque,” can lead to a great deal of death of nerve cells and progression of symptoms of Alzheimer’s disease (Genetics Home Reference, paragraph 6).

The Aβ plaques comprised of accumulated proteins that formed a β-sheet rich tertiary structure, promoting a self-assembling property and becoming cytotoxic. These resulting structures are very similar in from and function to amyloid fibrils. Though not the sole cause of the degeneration, this amyloid like structure is predicted to have a strong connection with the disease. Evidence has also been provided by this research group that these Aβ plaques have a highly similar de novo generation as many prion positive proteins. The Aβ aggregation begins with a seeding of misfolded proteins. In the case of Alzheimer’s disease these Aβ plaques spread through the brain’s tissue through axial propagation. This is shown when plaques are injected into a Aβ-rich brain and are seen to spread along the expected pathway of axons, from the hippocampus, to the hippocampal fissure, then the subpial zone. This research generated the conclusion that these Aβ plaques are essentially PrLPs. According to Walker the research also supports the designation that the seeds could be considered Aβ prions, as the molecular and protein properties of these match those given the yeast prions and other PrLP found throughout human disease.

Amyloid beta (Aβ) is a short peptide contains 37 to 43 amino acids and is well known for its hypothesized role in causing pathogenesis of AD, since one of the main hallmarks of AD is the accumulation of fibrillogenic Aβ in the grey matter of the brain (14-15). Meanwhile, over 90% of AD patients have cerebral amyloid angiopathy (CAA) which is characterized by the deposition of Aβ in capillaries, arteries, and arterioles (16-17). CAA causes the degeneration of smooth muscle cells and leads haemorrhages (17).

Autosomal dominant mutations in APP, PSEN1, or PSEN2 that alter APP processing and the production or self aggregation of Aβ, promote aggregation and accumulation of Aβ in brain causing early-onset AD (Bertram et al., 2010).

Studies have implicated astrocytic dysfunction in Alzheimer's disease (AD). However, the role of astrocytes in the pathophysiology and treatment of the disease is poorly characterized. Here, we identified astrocytes as independent key factors involved in several Alzheimer-like phenotypes in an APP/PS1 mouse model, including amyloid pathology, altered neuronal and synaptic properties, and impaired cognition. In vitro astrocytes from APP/PS1 mice induced synaptotoxicity as well as reduced dendritic complexity and axonal branching of hippocampal neurons. These astrocytes produced high levels of soluble