Pathogenesis - Alzheimer’s Disease

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Chapter: Medicinal Chemistry : Alzheimer’s Disease

It has referred that 11 amino acid sequence of ß-amyloid protein is neurotoxic for primary neurons. The cognitive deficits of patients with AD are closely associated with dysfunction of central cholinergic neurotransmission.


Pathogenesis

It has referred that 11 amino acid sequence of ß-amyloid protein is neurotoxic for primary neurons. The cognitive deficits of patients with AD are closely associated with dysfunction of central cholinergic neurotransmission. There is a selective neuronal loss especially on the basal forebrain, which project to hippocampus and neocortex. It is generally believed that there are reductions of muscarinic (mAChR) and nicotinic (nAChR) acetylcholine receptors, which are located on presynaptic cholinergic terminals. Acetylcholinesterase (AchE) has been shown to be promoting the assembly of ß-amyloid plaques into fibrils and is suggested to play a pathogenic role in AD by forming a complex, which has higher toxic effect than ß-amyloid protein. The oxidative deamination of amines generates neurotoxic agents, that is, NH3 and H2O2. Oxidative stress signalling is speculated in the pathology of AD and other neurodegenerative disorders. The free radicals produced during oxidative stress causes the DNA and RNA oxidation indicated by increased levels of 8hydroxy-2-deoxyguanosine and 8-hydroxy guanosine, elevated level of protein carbonyl residue and the lipid peroxidation, which are marked by higher levels of thiobarbituric acid reacting substance (TBARS), malondialdehyde (MDA), 4-hydroxy transneoneal (HNE), and isoprostrane. It is hypothesized that ß-amyloid protein accumulation and diffuse plaque formation is associated with local microglial activation, cytokine release, reactive astrocytosis, and a multiprotein inflammatory response. There is considerable evidence that the effects of ß-amyloid initiated inflammatory and neurotoxic processes, including excessive generation of free radicals and peroxidative injury to proteins and other macromolecules in neurons.

Of all persons with AD, up to 25% of cases are thought to be part of a familial-based inheritance pattern, and therefore, are only determined based on family history or genetic test results. In general, these forms of AD are inherited as an autosomal dominant disorder. There are indications that loss of glutaminergic neurons and glutamate activity in AD patients correlates with the severity of dementia, and glutaminergic disruption may be involved in the cognitive symptoms of this disorder. There is increasing speculation that AD may be linked aetiologically to the accumulation of aluminium in the brain. AD patients have inconsistently shown low concentration of norepinephrine, dopamine, and dopamine ß-hydroxylase. These are often considered to improve the fluency and creativity. Interactions between the serotonergic and cholinergic systems are deregulated and are believed to play a role in the mechanism underlying both major depression and AD.


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