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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Biochemistry of Alzheimer's disease | 5/5 | https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer's_disease | reference | science, encyclopedia | 2026-05-05T11:04:17.929946+00:00 | kb-cron |
=== Reelin hypothesis === A 1994 study showed that the isoprenoid changes in Alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of premature aging. During aging the human brain shows a progressive increase in levels of dolichol, a reduction in levels of ubiquinone, but relatively unchanged concentrations of cholesterol and dolichyl phosphate. In Alzheimer's disease, the situation is reversed with decreased levels of dolichol and increased levels of ubiquinone. The concentrations of dolichyl phosphate are also increased, while cholesterol remains unchanged. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of glycosylation in the diseased brain and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from oxidative stress, for instance induced by lipid peroxidation. Ropren, identified previously in Russia, is neuroprotective in a rat model of Alzheimer's disease. A relatively recent hypothesis based mainly on rodent experiments links the onset of Alzheimer's disease to the hypofunction of the large extracellular protein reelin. A decrease of reelin in the human entorhinal cortex where the disease typically initiates is evident while compensatory increase of reelin levels in other brain structures of the patients is also reported. Of key importance, overexpression of reelin rescues the cognitive capacities of Alzheimer's disease model mice and τ-protein overexpressing mice. A recent circuit level model proposed a mechanism of how reelin depletion leads to the early deterioration of episodic memory thereby laying the theoretical foundation of the reelin hypothesis.
=== Large gene instability hypothesis === A bioinformatics analysis in 2017 revealed that extremely large human genes are significantly over-expressed in brain and take part in the postsynaptic architecture. These genes are also highly enriched in cell adhesion Gene Ontology (GO) terms and often map to chromosomal fragile sites. The majority of known Alzheimer's disease risk gene products including the amyloid precursor protein (APP) and gamma-secretase, as well as the APOE receptors and GWAS risk loci take part in similar cell adhesion mechanisms. It was concluded that dysfunction of cell and synaptic adhesion is central to Alzheimer's disease pathogenesis, and mutational instability of large synaptic adhesion genes may be the etiological trigger of neurotransmission disruption and synaptic loss in brain aging. As a typical example, this hypothesis explains the APOE risk locus of AD in context of signaling of its giant lipoprotein receptor, LRP1b which is a large tumor-suppressor gene with brain-specific expression and also maps to an unstable chromosomal fragile site. The large gene instability hypothesis puts the DNA damage mechanism at the center of Alzheimer's disease pathophysiology.
== References ==