Alzheimers Disease

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Alzheimer's disease is an age-related cognitive disorder associated with oxidative brain damage. Those with Alzheimer's or other cognitive disorders have lower levels of antioxidants in their blood [6]. Individuals with Alzheimer's and Parkinson's diseases have decreased levels of reduced glutathione and increased levels of lipid peroxidation [3].

Accumulation of P-amyloid is associated with Alzheimer's disease development; its toxicity in cultures of hippocampal neurons is mediated via ROS, lipid peroxidation, activation of the caspase cascade, and apoptosis. When such cells were co-exposed to EGCG, incidence of the latter three events decreased in a manner independent of p53, Bax, Bcl-xL, and cyclooxygenase (COX) [7]. The cytotoxicity of amyloid proteins appears to rely largely upon the formation of well-ordered fibrillar assemblies. Polyphenols inhibit this formation independently of their antioxidant activity [8]. Iron chelation by EGCG also reduces the aggregation of a major component of neurofibrillary tangles, hyperphosphorylated tau, in the brains of these patients [9].

P-amyloid is formed after processing of amyloid precursor protein (APP) via a pathway requiring iron, which EGCG effectively chelates (see below). APP may alternatively be processed to form soluble APP, which blocks P-amyloid production;

EGCG promotes this pathway in a PKC-dependent fashion, increasing a-secretase activity [3]. EGCG also blocks the generation of P-amyloid-derived diffusible neurotoxin ligands and the associated apoptosis [10].

Malfunctioning of the glutamate neurotransmitter system is also involved in this disease [11]. P-amyloid-mediated neuronal death may involve the N-methyl-D-aspartate (NMDA) receptor for glutamate; receptor antagonists are clinically effective for Alzheimer's disease. EGCG effects both glutamate production and the increased cytoplasmic Ca+2 levels resulting from its binding to this receptor (see below).

ROS generation is partially dependent upon processes requiring intracellular iron, including the Fenton reaction. Dysregulation of cellular iron homeostasis, including uptake, distribution, transport, and storage, is a causal factor in the patho-genesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases and multiple sclerosis [12]. In the former, increased levels of iron and the transferrin receptor are found in the hippocampus and cerebral cortex, which may induce P-amyloid deposition as well as regulate APP mRNA posttranscriptionally, via iron regulatory proteins (IRP), or its translation, via an iron-responsive element. Several iron-chelating compounds are neuropro-tective; however, some are toxic and others do not easily penetrate the brain. EGCG is a highly effective iron chelator - but is nontoxic and readily enters the brain [12]. It reduces levels of holo-APP in mouse hippocampus and P-amyloid in neuroblastoma cells [12]. Iron chelation by EGCG increases levels of hypoxia inducible factor-1 (HIF-1), key to regulating induction of genes that protect against the deleterious effects of hypoxia, by interfering with its degradation by an iron-dependent proteosomal pathway [12]. Degradation of both HIF-1 and IRP is triggered by prolyl hydroxylase, an enzyme responsive to high levels of O2 and iron.

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