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Introduction
Alzheimer’s disease is a late-age congenital (since or even before birth) progressive neurodegenerative disorder, particularly affecting the brain at regions associated with higher mental functions such as neocortex and hippocampus region in forebrain. Pathologically, it manifests as extra-cellular deposits of β-amyloid proteins, derived by the action of enzymatic proteins, Precenilins, on amyloid precursor proteins (APP’s) produced in neurons.
These changes accompany an impairment of cognitive functions (memory, sense). Most of the investigations on amyloid plaques, a kind of neural coating, reveal presence of high amounts of unique Aβ proteins, whose amounts go up in diseased brain neurons. Two sub-types of this protein were immunologically detected and termed as Aβ42 and Aβ40. These changes bring about a cascade of events leading to inflammation and neuro-toxicity, which progress as release of harmful cytokines, neuritic membrane injury, ionic homeostasis, and oxidative injury.
Consequently, imbalance in protein kinase/phosphorylase signal transduction results in hyperphosphorylation and deformation of neurofibrilary micro tubular protein, known as tau, which leads to neurotransmitter deficits and dementia, a typical abnormal state of brain. The production and/or deposition of Aβ proteins in cerebral fluid and is linked with genetic mutations of at least four genes located in human chromosome #1, 14, 19 and 21 (Selkoe, 2001).
Review of literature
Six peer reviewed research articles related to genomic/proteomic analyses, and diagnostic aspects of Alzheimer’s are discussed. A complete genome analysis of Alzheimer’s disease was carried out by Kehoe et al. (1999). Usually, if proper markers for disease-related mutated genes are available, pre-natal prognosis of the disease through genetic counseling can be done. Such gene-associated markers have been characterized, in particular the apolipoprotein E gene, which was linked to chromosome# 19, and was responsible for accumulation of Aβ by way of binding to this protein. In this study, genome scan was carried out in 600 diseased sibling pairs.
Semi-automated fluorescent genomic mapping of each autosome and X chromosome, in which labeled marker DNA’s, corresponding to specialized chromosomal locations, called micro-satellites (specific repeats of consensus evolutionary DNA sequences), were used to detect presence of apolipoprotein E gene-linked marker. For this, lymphoblastoid cells (from leukocytes) were grown in cell culture medium, DNA was extracted and genomic analysis was done using a database.
It was revealed that apart from chromosome #19, apolipoprotein gene sub-types were also present in chromosome #1, 9 and 10. This suggests a high degree of linkage within the chromosome regions carrying apolipoprotein E gene. This finding can help in detection of the most causative gene or marker in chromosomes (#1, 9 and 10), other than what has been considered earlier (#19) for the detection process.
Another important and new discovery in this area has been to characterize the Alzheimer’s disease-specific protein biomarkers as diagnostic tools for early detection. According to Finehout, Franck, Choe, Relkin, & Lee (2007) a comparative proteomic analysis of cerebrospinal fluid, collected from diseased and healthy persons, gave clue on differential protein expression in the diseased tissue. Proteins from 34 patients and 34 normal control subjects were subjected to 2-dimentional electrophoresis, in which first dimension of protein separation is based on isoelectric points of the proteins, and then proteins are further resolved in second dimension by charge and molecular weights.
The proteins that were exclusively detected in the diseased samples were further identified by mass spectroscopic methods and by matching with protein database. Twenty three clear spots were found expressed in Alzheimer tissues. The prominent proteins identified were, Aβ transported proteins (including albumin), inflammation-related proteins, proteolytic enzyme inhibitors like anti-trypsin, and some neuronal membrane proteins. These are probably the largest ante mortem pathological biomarkers to be used for clinically relevant diagnostic assays.
Apart from genomic and proteomic diagnosis, anatomical methods like magnetic resonance imaging (MRI) of regions affected at very early stage can be used for early in vivo detection. Dickerson et al. (2001) carried out MRI to detect extent of hippocampal and entorhinal atrophy (wasting away of the tissue) in 34 healthy controls, 28 patients with cognitive complains not amounting to clinical dementia, and 16 patients with mild Alzheimer.
Mean normalized hippocampal and antorhinal volumes from both hemispheres were computed and statistically treated. The volumetric values significantly increased in both the affected groups compared to the controls, though the difference was not so significant between the two affected groups. Hence, the volumetric changes start much early even before mild cognitive impairment, such as age-associated memory loss. Such neuro-volumetric analysis would be useful anatomical biomarker for early diagnosis.
As mentioned, apolipoprotein proteins are related to Aβ proteins deposition, whose serum level can be monitored as biochemical biomarker for early diagnosis. Merched, Xia, Visvikis, Serot & Siest (2000) carried out an investigation on relative concentration of this protein in serum. For this, blood from 98 patients and 59 healthy elderly people were analyzed for cholesterol, triglycerides, and serum apolipoprotein A and B, the later by immunological methods.
The serum apolipoprotein A, but not B, was quite low in serum collected from diseased compared to healthy controls. Another interesting feature was that in patients, with mutated apolipoprotein E genes and who are more prone to the disease, the serum level of apolipoprotein A correlated with severity of Alzheimer’s disease. As this protein level goes up in cerebrospinal fluid in the patients, it was proposed that enhanced passage from blood to brain fluid may account for decrease level in serum.
In another study, serum homocysteine level, generally known to be associated with cardiovascular diseases, has been shown to correlate with general dementia and Alzheimer’s disease (Seshadri et al., 2002). Plasma total homocysteine level was measured in 1092 subjects without dementia. Within eight years, those individuals having >14 µmol L-1 baseline value, exhibited clinical symptoms of the disease and dementia.
Lower serum of folate a vitamin precursor and vitamin B6 and B12 are associated with elevated homocysteine level, but their levels could not be associated with the progression of the disease. Interestingly, this attribute was independent of the risk prone genotype and every population had the homocysteine-related development of dementia. Hence, plasma total homocysteine appears to be another crucial biochemical marker for both cardiovascular and Alzheimer’s diseases.
Several independent lines of study suggest that toxicity and neuro-degeneration action of Aβ proteins is mediated through production of reactive oxygen species (ROS). Hence, enzymes that quench ROS also protect neurotoxicity. One such enzyme discovered is NAD(P)H:quinone oxidoreductase (QR). In a study post-mortem tissue were obtained from 6 patients and 5 healthy persons (Wang, Santa-Cruz, DeCarli & Johnson. 2000).
After tissue homogenization, the QR level was determined by immunohistochemical straining and by Western blot analysis, using specific anti-serum raised against QR. The hippocampal neurons stained heavily in the patients’ samples, but not in controls. In accordance to this result, the patients’ brain samples also positively reacted with anti-QR-antibody, while much lower cross-reactivity was found in healthy controls. Hence, QR level can become another important enzyme-marker and can be adopted to use ante mortem for an early diagnosis of Alzheimer’s disease.
Conclusion
The biochemical and genetic basis of Alzheimer’s disease and associated dementia were discussed, and six articles related to genomic, proteomic, anatomical and biochemical markers for early detection were reviewed. The genetic marking of the prone-population is possible by epidemiological and anthropological investigations. Proteomic markers can further verify the onset and progression of disease in the prone population. Biochemical biomarkers and anatomical imaging can help confirm the disease symptoms, not only in prone but also in those populations in which other abnormalities are associated with dementia. Finally, new drugs can be designed and their efficacy can be monitored at preclinical and clinical trials.
References:
Dickerson, B.C., Goncharova, I., Sullivan, M.P., Forchetti, C., Wilson, R.S., Bennett, D.A., et al. (2001). MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer’s disease. Neurobiology of Aging, 22, 747–754.
Finehout, E.J., Franck, Z., Choe, L.H., Relkin, N., & Lee, K.H. (2007). Cerebrospinal fluid proteomic biomarkers for Alzheimer’s disease. Annals of Neurology, 61, 120–129.
Kehoe, P., Vrieze, F.W., Crook, R., Wu, W.S., Holmans, P., Fenton, I, et al. (1999). A full genome scan for late onset Alzheimer’s disease. Human Molecular Genetics, 8 (2), 237-245.
Merched, A., Xia, Y., Visvikis, S., Serot, J.M., & Siest, G. (2000). Decreased high -density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer’s disease. Neurobiology of Aging, 21, 27–30.
*Selkoe, D.J. (2001). Alzheimer’s disease: Genes, proteins, and therapy. Physiological Reviews, 81 (2), 741-766.
Seshadri, S., Beiser, A., Selhub, J., Jaques, P.F., Rosenberg, I.H., D’Agostino, R.B., et al. (2002). Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. The New England Journal of Medicine, 346 (7), 476-483.
Wang, Y., Santa–Cruz, K., DeCarli, C., & Johnson, J.A. (2000). NAD(P)H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Alzheimer’s disease. Neurobiology of Aging, 21, 525–531.
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