TITLE ABSTRACT Alzheimer’s Disease (AD) has been implicated with two major pathologies, the accumulation of amyloid-B and tau phosphorylation (_). These pathologies have long been implicated with the gene Alipoprotein E (ApoE) which continually showed a dosage-dependent effect on amyloid-B clearance (_). Many studies have shown correlated linkage between ApoE and tau as well as their possible interactions (_). Tau phosphorylation has continually been found among many AD patients suffering with and without amyloid-B deposition (_). However, it is still unclear whether ApoE affects tau pathology separately from amyloid-B. Shi et al. aimed to conduct an experiment to show the direct association of ApoE to taupathy while eliminating the …show more content…
The three alleles of ApoE (E2, E3, and E4) have been found to show dosage-dependent effects that negatively affects the clearance of amyloid-B plaque, with E4 showing the least clearance whereas E2 being protective (Deane et al., 2008; Holtzman, 2004). Additionally, the increasing amount of E4 alleles increase the risk for AD and lowers the age of onset among late onset familial AD patients (Corder et al., 1993). 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. However, a possible mechanism by which ApoE interact with tau proteins have been demonstrated. Paired helical filaments in NFTs often contain
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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
Alzheimer’s is a progressive, irreversible disease that deteriorates parts of the brain, attacking neurons and nerve cells. This results in the loss of important mental functions, especially memory (Alzheimer’s Foundation of America). This disease is detrimental, both to the individual and their friends and family. Alzheimer’s is also a very dangerous disease, as those living with the condition may forget how to drive while operating a motor vehicle, forget where their home is or even forget how to breathe. Not only is Alzheimer’s a progressive and devastating disease, but is also genetic. Research has been pooling out in ways to test individuals for the Alzheimer’s gene – ApoE4 is the genetic variant that triples the risk of developing Alzheimer’s
The disease called Alzheimer’s is the fourth leading cause of death in the United States (Weiner, 1987). It is estimated that the elderly population will double between now and 2030. During this period, the number of elderly will grow by an average of 2.8% annually (U.S. Census Bureau, 2001). By 2050, the number of people with Alzheimer’s is estimated to range from 11.3 million to 16 million (Alzheimer’s Association, 2005). These startling numbers should prompt an examination into one of the leading causes of death among this group of people. Understanding what Alzheimer’s is and the known causes of the disease are a good starting point. For those who have aging family members, knowing the risk factors and warning
Scientists believed in 1995 that there was a genetic influence in over half the cases of Alzheimer's disease. The gene scientists are giving the most consideration to apolipoprotein E gene (ApoE) as the main gene involved in the development of Alzheimer's disease. Everyone has this gene; if they did not, they would not be alive. ApoE carries a person's cholesterol through their blood. The effect that this gene has in terms of the brain is not totally understood. Scientists have found that
Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disease and the most common cause of dementia. Finding the potential genes involved in AD is an essential step in molecular diagnosis and is important to understand the mechanisms leading to neurodegeneration. The genetics of early-onset AD (EOAD) are largely understood with mutations in three different genes. In contrast, the genetics of late-onset Alzheimer’s disease (LOAD) are not fully understood. LOAD is much more common and far more complex than EOAD because of the involvement of numerous genetic, epigenetic and environmental factors. The apolipoprotein E (APOE) ε4 allele has been found to be a main risk factor for LOAD. Genome-wide association studies (GWASs)
The Journal of the American Medical Association reports the latest break through in the study of gene causing Alzheimer’s has pointed to two genes, chromosomes 2 and 19 that cause the disease (7). The article also points out another gene, A polipoprotein E-e4, is also linked to Alzheimer’s disease. According to the Journal of Alzheimer’s disease, Jose Vina and Ana Lloret writes that women are at higher risk of Alzheimer’s due
The strongest genetic risk factor for late onset AD is APOE, a locus that is found on chromosome 19. (Corder, 1993) APOE can be found as three different alleles (APOE-2/3/4), but APOE-3 is the most common allele, as it occurs in 72% of the population. (Karch, 2014) While early onset AD mutations in APP lead to an altered production of Aβ isoforms in the brain, APOE influences Aβ by affecting its aggregation and clearance process. APOE-4 binds to Aβ much more rapidly than other APOE alleles, which accelerates fibril formation and increases the odds of neurofibrillary tangles; furthermore, APOE also regulates Aβ metabolism. The combination of these facets allows APOE to influence the amount and structure of intraparenchymal Aβ deposits.
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by β-amyloid plaque formation caused by aggregation of β-amyloid42 within the brain leading to a progressive decline in cognitive function and memory loss (2). Hyperphosphorylated tau protein is occasionally found in brains of AD patients with advanced pathology however, it is not necessarily an indicator of AD but considered a sign of disease severity (2, 4, Kosik et al, 1986). AD is separated into two subcategories following the simple sporadic and familial disease classifications, early-onset AD (EOAD) which develops in individuals between 30 and 60+ years of age and late-onset AD (LOAD) which develops in individuals 60 years of age or older (2). Familial AD may
Alzheimer’s disease is the most common form of dementia and is characterized by the degeneration and death of brain cells that causes a loss of mental function. Although neuronal loss is not considered a normal part of aging, age is a significant risk factor for Alzheimer’s disease (AD) (Lindsay et al., 2002). Hallmarks of AD include tau tangles and Amyloid-β plaques, whose interaction is thought to lead to neuronal death (Ittner & Götz, 2011). At present, there is no singular cause identified for AD, and further study is required before a cure can be developed. One proposed link to AD is a mutation in Microtubule Associated Protein Tau (MAPT), coded by the MAPT gene located on chromosome 17 (Lee, Goedert, & Trojanowski, 2001). Tau protein is normally soluble and functions to stabilize microtubules within axons. However, mutations in MAPT can cause Neurofibrillary Tangles (NFTs) comprised of hyper-phosphorylated tau protein to collect within neurons and spread throughout the brain (Clavaguera et al., 2009). These tau tangles are detergent-insoluble and impair axonal transport to an extent (Zhang et al., 2012). Transgenic mice expressing mutant human P301S tau protein exhibit synaptic dysfunction followed by hippocampal and cortical neuronal loss (Yoshiyama et al.,
In regards to Alzheimer’s disease, there are two types of the disease: sporadic and familial. Sporadic Alzheimer’s disease occurs when the disease develops with no one in the affected individual’s family having had it before. Familial Alzheimer’s disease occurs when the affected individual has a family history of Alzheimer’s disease and develops the disease due to this predisposition. It is thought that the APOE-4 gene, or apolipoprotein E-4, is responsible for familial alzheimer’s disease, as it has been shown to be present in over half of the population of those with Alzheimer’s disease and to potentially be the cause of increased plaque production within those who have the gene.
Subsequent studies in animal models for insulin resistance, AD, or both, have established that insulin resistance exacerbates Aβ and tau phenotypes including enhanced Aβ 42/40 ratio, total tau, and hyperphosphorylated tau (Ho et al., 2004; Lester-Coll et al., 2006; Li et al., 2007; Masciopinto et al., 2012; Plaschke et al., 2010; Qu et al., 2011; Searcy et al., 2012; Takeda et al., 2010) and AD amyloidosis models exhibit insulin resistance (Rodriguez-Rivera et al., 2011).
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).
In late onset Alzheimer's case, the genetic test involves a simple blood test, revealing whether the patient has apolipoprotein E (APOE) alleles, which may increase the risk of Alzheimer's onset. There are three types of APOE alleles: E2, E3 and E4. The E2 allele has shown a reduced risk of late onset Alzheimer's. The E3 allele is the most common and has no effect on chances of having alzheimer's. On the other hand, the E4 allele increases the
A growing body of evidence has indicated that sAD is multifactorial, with age being an important risk factor. Main neuropathological hallmarks identified in Alzheimer’s brains are beta-amyloid deposits, hyperphosphorylated tau proteins, and astrogliosis . Recently, dysregulated brain insulin signaling has been reported to play a pivotal role in AD pathology. Additionally, several studies have indicated that insulin malfunction induces beta amyloid accumulation and tau pathology in AD brain . Thus, Alzheimer’s disease has been argued to be a type III diabetes [3, 4]. Given the specific nature of sAD, there is no clinical evidence on its early stage, and this makes making an appropriate model more difficult. Thus, a convenient model for the initiation phase of sAD could be the
Till date, the molecular mechanisms associated with AD have remained elusive and no drug can reverse the pathological process . Since the clinical diagnosis of AD is currently based on qualitative often subjective, the need for a sensitive, specific and reliable markers to diagnose and monitor the disease progression in AD is essential. The biomarkers evaluated to date, including CSF levels of total tau, phosphorylated tau and amyloid-β₄₂ (Aβ₄₂) unfortunately have not shown the accuracy and reliability