How does the elderly chromosome behave? Part-2
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Mutations are the main reason for early onset of AD dementia. This happens mainly in three specific genes. One is amyloid precursor protein gene (APP) which encodes with the neuronal membrane protein APP from which β-amyloid (A-β) is released. This happens with the help of two proteases, β-secretase and gamma-secretase. The other two genes responsible for AD are presenilins 1 and 2.However, they are rare. The ApoE E4 allele is associated with an increased risk of late onset AD and the ApoE E2 allele with reduced risk. However, sometimes it may not develop AD. It has also been seen that many people without an ApoE4 allele do get AD.
Recently, studies have shown the beginning to link specific genetic risk factors to components of the AD phenotype which includes cognitive profile, structural changes on imaging and even on CSF biomarkers. Much research is also taking place to study the pathogenic events in AD. APP is the precursor protein for A-β. Mutations in APP increase the production of A-β. AD is also caused when this gene triplicates. This leads to an increase in APP. It has been found that patients with Down syndrome usually have a third copy of APP by virtue of trisomy 21 and due to this they develop age-dependent amyloid deposition and dementia. All the three disease genes have been associated in the production or accumulation of amyloid. Mutations in tau cause frontotemporal dementia (FTD) / frontotemporal lobar degeneration (FTLD).
The biomarkers are helpful in diagnostic and prognostic makings. Currently A-β and tau levels in the CSF are mostly used for the accuracy of diagnosing AD versus other forms of dementia.
AD also affects the immune system and neuroinflammation. It has been seen that there is an up-regulation of the components of in neurofibrillary tangles and neurotic plaques. For neurological function regulation of cholesterol homeostasis is very important or otherwise it may cause neurodegeneration. Clusterin binds to Aβ, lipids and complement factors and helps in the transport of cholesterol and phospholipids.
Growing evidence shows that it is possible to identify biomarkers of the disease earlier to the cognitive symptoms in a person. This could improve our ability to find effective drugs that slow the rate of disease or stop it altogether.
Synucleinopathies include the overlapping spectrum of Parkinson’s disease (PD) which is PD with dementia and dementia with Lewy bodies. Lewy bodies are present in the substantia nigra and some parts of the brain stem. AD genes (Apo E, CLU, CR1, CD33, ABCA7 and MS4A) have been found to be directly or indirectly involved in the regulation of inflammatory mechanisms.
Clusterin binding may represent a way to protect cells against aggregating proteins by binding to fibrillar proteins which prevents the inflammatory response. It is also important that cholesterol homeostasis is regulated for neurological function. Genes ApoE and clusterin take part in the formation of lipoprotein particles across the blood brain barrier and also transport. Dysregulation of cholesterol and sterol related compounds increase the formation of arterial plaques and indirectly the risk of heart disease and AD.
Connections between immune and lipid pathways have been found in these pathogenesis. It has also been found that if any genetic mutations take place they may in turn alter the transporter function which impacts the lipid transport, brain function and there can be neurodegeneration. Frontotemporal lobar degeneration (FTLD) can be either genetic or neurodegenerative disorder where the frontal and temporal lobes degenerate. This usually happens before AD.
Scientists are working on the expansion of hexanucleotide where the disease may be caused by a dominant RNA toxicity. Recently, scientists have shown that inclusion body myopathy is associated with Paget disease of bone and/or frontotemporal dementia” (IBMPFD). The symptoms include spine or hip pain, pathological fractures or deformities in long bones and increase in alkaline phosphatase content.
Inherited mutations in the prion gene causes Creutzfeldt-Jakob disease (CJD) and other prion disorders that include Gerstmann-Straussler-Scheinker disease (GSS) and fatal familial insomnia. When a brain MRI shows disturbances in the white matter than it is advised to look into the history of strokes, migraine, multiple sclerosis, dementia or migraine. Patients with Huntington’s disease (HD) have a pathogenic CAG repeat expansion which ends up in dementia.