PMC:4034082 / 46096-52963 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4034082","sourcedb":"PMC","sourceid":"4034082","source_url":"http://www.ncbi.nlm.nih.gov/pmc/4034082","text":"2.3. Functional Genomics\nOver 80% of the genes which conform the structural architecture of the human genome are expressed in the brain in a time-dependent manner along the lifespan. The cellular complexity of the CNS (with 103 different cell types) and synapses (with each of the 1011 neurons in the brain having around 103–104 synapses with a complex multiprotein structure integrated by 103 different proteins) requires a very powerful technology for gene expression profiling, which is still in its very early stages and is not devoid of technical obstacles and limitations [95]. Transcripts of 16,896 genes have been measured in different CNS regions. Each region possesses its own unique transcriptome fingerprint which is independent of age, gender and energy intake. Less than 10% of genes are affected by age, diet or gender, with most of these changes occurring between middle and old age. Gender and energy restriction have robust influences on the hippocampal transcriptome of middle-aged animals. Prominent functional groups of age- and energy-sensitive genes are those encoding proteins involved in DNA damage responses, mitochondrial and proteasome functions, cell fate determination and synaptic vesicle trafficking. The systematic transcriptome dataset provides a window into mechanisms of neuropathogenesis and CNS vulnerability [96]. \nFunctional genomics studies have demonstrated the influence of many genes on AD pathogenesis and phenotype expression. The study of genotype-phenotype correlations is essential for the evaluation of the actual impact of specific polymorphic variants of a particular gene on the clinical manifestation of the disease and/or biological markers reflecting the disease condition or different biological states of the individual. Mutations in the APP, PSEN1, PSEN2, and MAPT genes give rise to well-characterized differential neuropathological and clinical phenotypes of dementia [8,20,21]. APP mutations are associated with AD1, early-onset progressive autosomal recessive dementia, early-onset AD with cerebral amyloid angiopathy, and hereditary amyloidosis with cerebral hemorrhage Dutch type, Italian type, or Iowa type. PSEN1 mutations are associated with the phenotypes of familial AD3, familial AD3 with unusual plaques, familial AD with spastic paraparesis and unusual plaques, familial AD with paraparesias and apraxia, frontotemporal dementia, Pick’s disease, and dilated cardiomyopathy. MAPT mutations are associated with frontotemporal dementia, frontotemporal dementia with parkinsonism, Pick’s disease, progressive supranuclear palsy, progressive atypical supranuclear palsy, tauopathy and respiratory failure [8]. \nTransgenic animals also reproduce to some extent the neuropathological hallmarks of AD in a sequential manner. The triple transgenic mouse model of AD (3xTg-AD) harbors three AD-related loci: human PS1M146V, human APPswe, and human MAPTP301L. These animals develop both amyloid plaques and NFT-like pathology in a progressive and age-dependent manner in hippocampus, amygdala, and cerebral cortex, the main foci of human AD neuropathology. The evolution of AD-related transgene expression, amyloid deposition, tau phosphorylation, astrogliosis, and microglia activation throughout the hippocampus, entorhinal cortex, primary motor cortex, and amygdala over a 26-month period has been immunohistochemically documented. Intracellular Aβ accumulation is the earliest of AD-related pathologies to be detectable, followed temporally by phospho-tau, extracellular Aβ, and finally paired helical filament and NFT pathology [97]. In the same model, a decrease in neurogenesis directly associated with the presence of amyloid plaques and an increase in the number of Aβ containing neurons in the hippocampus has been demonstrated [98].\nDifferent APOE genotypes also confer specific phenotypic profiles to AD patients. Some of these profiles may add risk or benefit when the patients are treated with conventional drugs, and in many instances the clinical phenotype demands the administration of additional drugs which increase the complexity of therapeutic protocols. From studies designed to define APOE-related AD phenotypes [6,7,8,9,10,11,12,13,14,15,16,17,99,100,101,102,103,104], several confirmed conclusions can be drawn: (i) the age-at-onset is 5-10 years earlier in approximately 80% of AD cases harboring the APOE-4/4 genotype; (ii) the serum levels of ApoE are lowest in APOE-4/4, intermediate in APOE-3/3 and APOE-3/4, and highest in APOE-2/3 and APOE-2/4; (iii) serum cholesterol levels are higher in APOE-4/4 than in the other genotypes; (iv) HDL-cholesterol levels tend to be lower in APOE-3 homozygotes than in APOE-4 allele carriers; (v) LDL-cholesterol levels are systematically higher in APOE-4/4 than in any other genotype; (vi) triglyceride levels are significantly lower in APOE-4/4; (vii) nitric oxide levels are slightly lower in APOE-4/4; (viii) serum Aβ levels do not differ between APOE-4/4 and the other most frequent genotypes (APOE-3/3, APOE-3/4); (ix) blood histamine levels are dramatically reduced in APOE-4/4 as compared with the other genotypes; (x) brain atrophy is markedly increased in APOE-4/4 \u003e APOE-3/4 \u003e APOE-3/3; (xi) brain mapping activity shows a significant increase in slow wave activity in APOE-4/4 from early stages of the disease; (xii) brain hemodynamics, as reflected by reduced brain blood flow velocity and increased pulsatility and resistance indices, is significantly worse in APOE-4/4 (and in APOE-4 carriers, in general, as compared with APOE-3 carriers); (xiii) lymphocyte apoptosis is markedly enhanced in APOE-4 carriers; (xiv) cognitive deterioration is faster in APOE-4/4 patients than in carriers of any other APOE genotype; (xv) occasionally, in approximately 3-8% of the AD cases, the presence of some dementia-related metabolic dysfunctions (e.g., iron, folic acid, vitamin B12 deficiencies) accumulate more in APOE-4 carriers than in APOE-3 carriers; (xvi) some behavioral disturbances (bizarre behaviors, psychotic symptoms), alterations in circadian rhythm patterns (e.g., sleep disorders), and mood disorders (anxiety, depression) are slightly more frequent in APOE-4 carriers; (xvii) aortic and systemic atherosclerosis is also more frequent in APOE-4 carriers; (xviii) liver metabolism and transaminase activity also differ in APOE-4/4 with respect to other genotypes; (xix) blood pressure (hypertension) and other cardiovascular risk factors also accumulate in APOE-4; and (xx) APOE-4/4 are the poorest responders to conventional drugs. These 20 major phenotypic features clearly illustrate the biological disadvantage of APOE-4 homozygotes and the potential consequences that these patients may experience when they receive pharmacological treatment 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