Biology : Biology And Biology

Alzheimer 's disease (AD) was discovered by a German doctor Alois Alzheimer in 1906 when he found amyloid plaques and neurofibrillary tangles in the autopsy of a woman who died of an unknown mental disease. The extracellular amyloid plaque deposits, composed of insoluble amyloid-Beta peptide were hypothesized to be the main etiological factor. “The most important abnormality is an excess of Amyloid-beta peptides brought about through either overproduction or failure in degradation.” (Uzun, Kozumplik, & Folnegović-Smalc, 2011) Later, it was discovered that intracellular neurofibrillary tangles composed of hyper-phosphorylated, helically-paired tau

It is a disease that we haven’t cured yet but instead have only come up and still coming up with treatment strategies to alleviate its symptoms. AD was first described in 1906 by a German psychiatrist by the name of Alois Alzheimer whilst he was performing a histophathologic study of his patient’s brain, a patient who had been suffering from dementia. His patient’s brain’s autopsy brought to light the presence of two types of lesions, which are senile plaques and neurofibrillary tangles. He saw a visible difference in the brain tissue for it was severely damaged by these lesions. Since then, our knowledge of AD’s cellular and molecular alterations has increased and we have come up with various hypotheses for AD that may soon help in developing effective preventative and therapeutic strategies. One of the most prevailing hypotheses that have already leaded to a number of therapeutic approaches is the amyloid cascade hypothesis. Hence, the following essay will explore the pathology of the amyloid cascade hypothesis and the evidence for and against it. It will also touch upon current progress in clinical trials that test the

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.

Alzheimer’s disease is named after Dr. Alois Alzheimer who first discovered deviations from normal tissues of healthy individuals in the brain tissue of a lady in 1906. The woman, who showed symptoms of erratic behavior, loss of memory, and problems with communication, died of a then unfamiliar mental disorder. This led Dr. Alzheimer to investigate the cause of her unusual death. He assessed the brain of the woman and found that there were many anomalous masses (amyloid plaques) and intertwined bundles of fiber (neurofibrillary tangles). Scientists today have pinpointed the qualities of Alzheimer’s to be a) tangles in the brain (neurofibrillary tangles), b) plaque in the brain (amyloid plaques), and c) loss of connections among nerve cells.

Cognitive impairment associated with Alzheimer’s disease occurs when synapses, which transmit information from one neuron to another, become interrupted and communication ceases (7). The result is death of the nerve cell within the brain, also referred to as synaptic failure (6). Synaptic failure takes place when amyloid plaque and neurofibrillary tangles develop (7). Amyloid plaque develops from amyloid beta proteins, which are released by enzymes from the amyloid precursor protein that is located on the surface of the neuron (7). The amyloid beta proteins are normally cleared within the body once they are released however, in

Damage or lesions to the brain are the main causes of Alzheimer’s disease; the two main causes of these lesions are neurofibrillary tangles and senile plaques. (4) These are commonly known as plaques and tangles and are caused by the build-up of two proteins. The plaques are a build-up of the protein beta-amyloid (β-amyloid) while the tangles are formed by the build-up of the protein tau, even though both are found in Alzheimer's disease only the β-amyloid plaques are unique to the disease and it is these plaques that are believed to be the primary cause of Alzheimer's.

(APP). APP is cleaved by two different enzymes to produce one amyloid beta monomer, which aggregates with other monomers to form cytotoxic

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

The effects of the accumulation of amyloid-β plaques in AD have been more thoroughly researched than the other possible driver of AD, tau pathology (Kim et al., 2009). It was observed that tau seemed to be a better predictor of dementia than amyloid-β plaques (Brier et al., 2006), showing the importance of tau pathology research. While many studies have already shown the interaction of ApoE and amyloid-β driving AD, the relation between ApoE and tau is still unclear. Some studies have suggested that amyloid-β may be driving the hyperphosphorylation of tau and thus, the formation of NFTs downstream in the progression of AD (Lewis et al., 2001; Götz et al., 2001; Oddo et al., 2004). Because of the strong association between ApoE and amyloid-β, it may be that ApoE influence tau indirectly through the presence of amyloid-β plaques.

Two structural abnormalities have been found in the brains of Alzheimer patients. The first is Amyloid plaques which are clusters of protein fragments (Aβ-peptide) that come from a protein called amyloid precursor protein (APP), which is

PSEN1 and PSEN2 are polytopic membrane proteins (Davis et.al., 1998) that form the catalytic core in the protease γ-secretase (Francis et.al., 2002), which is responsible for the proteolysis of APP (Navivaeva & Turner, 2013). When there is a mutation at the loci for PSEN1 and PSEN2, located on chromosome 14 and 1 respectively, the activity of γ-secretase is altered resulting in changes in the proteolysis of APP and increased formation of Aβ (Qain et.al., 1998). Due to the increase of Aβ, amyloid plaques aggregate quickly causing early-onset of AD.

the pathogenic mechanism of presenilin mutations which alters APP metabolism would be responsible to elevate levels of Aβ peptides. (Bertram and Tanzi, 2008). followed by APOE, a major genetic risk factor increase Aβ peptide aggregation and impair Aβ clearance in the brain for the disorder in the typical late-onset period (Strittmatter and Roses, 1995). The genetic studies suggest that neurodegenerative processes in AD are the consequences of an imbalance between Aβ peptide production and clearance. However, physiological functions of APP are poorly understood (Yoshikai et al., 1990; Ling et al., 2003; Muller and Zheng, 2012). The APP gene is located on chromosome 21 and those individuals suffer from Down's syndrome (trisomy 21) with an extra copy of this chromosome develops an early-onset familial AD (EOFAD) (Yoshikai et al., 1990; Ling et al., 2003). There are two proteolytic processing pathways of APP. In the non-amyloidogenic pathway, APP cleaved by α and γ secretases resulted in the production of soluble form of APP (sAPPα). In amyloidogenic pathway, APP cleaved by β-secretase generates membrane bound C-terminal fragment (C99) which subsequently cleaved by γ secretase and produces Aβ peptide (Nunan and Small, 2000; Selkoe and Schenk, 2003).

Importantly synaptic dysfunction occurs early in AD, while actual loss of synapses does not appear until much later in the disease. The loss of synaptic density leads to inhibition of the excitatory transmission in both the hippocampus and cerebral cortex, leading to significant memory loss [54, 55]. Although Aβ deposition and tau phosphorylation may induce neuronal loss, the predominant mechanism accounting for-synaptic thinning is more likely progressive neuronal apoptosis. Several factors have been shown to stimulate apoptosis in various models of AD, including, impaired glucose metabolism, excitotoxicity and mitochondrial dysfunction. Additionally, factors, such as tumor suppressor protein p53, forkhead box protein (FOXO), and ROS, can mediate apoptosis in AD [56, 57]. Thus, new treatment strategies aimed at developing molecules that downregulate apoptosis are currently a primary

Another important consequence of heightened levels of Aβ 42 is the disruption of astrocytes responsible for regulating Ca2+ levels in the extracellular space of neurons which is essential for Ca2+ cascades. When Aβ 42 oligomers are released from neurons, they can bind to receptors on partner astrocytes and cause the astrocytes to release glutamate which is then taken up by NMDA receptors. The resultant signal cascade causes surges in Ca2+ evoking a cascade of events, including oxidative damage from dysfunctional mitochondria, tau hyperphosphorylation, the destruction of dendritic spines and neuronal synapses, and severing communications within the astrocyte’s neurons and beyond (Kumar et al., 2015).

It has been found that the oligomeric forms of Aβ were more dangerous than its monomers, acting intracellularly and extracellularly leading to the disruption of several downstream mechanisms, such as the disruption of intracellular calcium homeostasis (Camandola