**7. Membrane phospholipid metabolism**

onset sporadic AD (LO-SAT). The critical factors seem to be the ratios of polyunsaturated fatty acids (PUFAs) to monounsaturated (MUFA), saturated fatty acids (SFA) to essential

Oxidation of neuronal lipid membranes could be the initiating event in the cascade of synergistic processes with subsequent expression of Aβ and helical filaments of hyper‐ phosphorylated tau protein. PUFAs are important in modulating the inflammatory bal‐ ance/systemic anti-inflammatory eicosanoids and fluidity and membrane function. Proinflammatory eicosanoids are derived from arachidonic acid (AA). The anti-inflamma‐ tory eicosanoids are derived from the via the n-3 EFA through DHA) and EPA. EFAs cannot be synthesized by animals and must be obtained from food. A diet rich in linole‐ ic acid promotes proinflammatory state, while a diet rich in linolenic acid promotes in‐ flammatory components. When lipids are exposed to free radicals begin an autoperoxidative process. This process is perpetual and changes the composition and rate of membrane lipids with loss of PUFA compared with MUFA and SFA. This causes the membrane to become less fluid and affecting the function of components, as well as of intracellular organelles and the vascular endothelium [106]. This seems to be the ini‐ tial process of the cascade that culminates in neuronal death and neuropathological se‐ quelae associated with LO-SAT. Antioxidant vitamins and vegetables may reduce the risk of AD. High levels of blood lipids are associated with atherosclerosis and diabetes, both risk factors for EA indirect. Recently it was found that the increase in LDL choles‐ terol, along with APOE epsilon4 genotype is associated with increased risk of AD [107]. The oxidative state of lipid membranes can have effects on neurons, at three levels:a) vascu‐ lar;b) endothelial cell membrane; and c) membrane organelles.At the level of cellular mem‐ branes lipid oxidation accelerates the aggregation of amyloid which consequently decreases membrane fluidity. This also is observed with decreases of the content of MUFA and PUFA esterified to phospholipid. Interestingly, these changes are seen in brain regions affected in AD, especially at the hippocampus. The decrease of the membrane fluidity affects the syn‐ aptic connections [108]. The EA may be preventable and treatable and possibly reversible to some extent, if the proposed hypothesis is correct. The changes in the fat composition of the diet are reflected in plasma lipids and phospholipids in the membrane of red blood cells, likewise in the neural cell membranes, especially in areas of rapid lipid turnover. A diet low of n-6 PUFA and MUFA, and an adequate amount of n-3 PUFA, but not too caloric, with antioxidants should protect neuronal damage, lipid oxidation and the inflammatory cascade

Lipid lowering agents appear to have a protective effect, although studies are not conclu‐ sive. Statins decrease the oxidizability of LDL, with decreased levels of oxygen reactive spe‐ cies, anti-inflammatory effects and improve endothelial dysfunction, also increased alphasecretase activity. Increase the synthesis of LDL receptors, with decreased circulating level

The histological changes seen in the initial stages of AD confirmed that membrane lipids and inflammation are involved in the disease (Figure 7). AGE n-3/n-6 rate has a major impact on the balance of eicosanoid metabolism inflammatory and anti-inflammatory,

fatty acids (EFAs). These contents are modified by the APOE4 genotype [105].

and amyloid deposition.

160 Understanding Alzheimer's Disease

and reduced production of PPA.

The principal constituents of mammalian cell membranes are phospholipids, the most abundant of which is phosphatidylcholine (PC). PC biosynthesis is initiated by the phos‐ phorylation of choline to form phosphocholine, which then combines with cytidine tri‐ phosphate (CTP) to form 5'-cytidine diphosphocholine (CDP-choline); this compound then reacts with diacylglycerol (DAG) to produce PC [110]. The rate at which cells form PC is affected by the availability of its precursors. Thus, uridine or cytidine increase CTP levels [111]; availability of CTP levels in turn can be rate-limiting in the syntheses of CDP-choline [112] and PC [113]; and DAG levels can control the conversion of CDP-chol‐ ine to PC [114]. AD is also associated with abnormal metabolism of membrane phospho‐ lipids. Alterations in the metabolism of the phospholipids phosphatidylcholine (PC) have been detected in the cerebrospinal fluid of AD patients [115]. Neural membrane glycero‐ phospholipids, particularly ethanolamine plasmalogens, are markedly decreased in au‐ topsy samples from AD brain compared to age-matched control brain [116]. This decrease in glycerophospholipids is accompanied by a marked elevation in phospholipid degradation metabolites such as glycerophosphocholine, phosphocholine, and phosphoe‐ thanolamine [117]. Furthermore, marked increases have been reported in levels of prosta‐ glandins and lipid peroxides in AD brain [118,119]. The marked changes observed in phospholipids and their catabolic products may be coupled to the elevated activities of lipolytic enzymes in AD brain [120]. Moreover, cortices of AD patients have decreased levels of PC and phosphatidylethanolamine, compared with age-matched controls [116]. PC synthesis is regulated by levels of its precursors [113,114]; therefore, stimulation of PC synthesis by increasing precursor levels prevents the disruption in normal phospholi‐ pid metabolism caused by AD. Furthermore, increasing cell membrane synthesis may have morphological consequences for the cell. For instance, dendritic atrophy and loss occur in mouse models of AD [121,122] and dystrophic neurites are observed in human cases of AD [123]

**Author details**

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### **8. Concluding remarks**

Data from a series of biochemical, genetic, epidemiological studies and others exhibited that cholesterol is a key factor in APP processing and Aβ production. For instance, high cholesterol levels are linked to increased Aβ generation and deposition. It appears that there are many different ways in which abnormalities in cholesterol metabolism can af‐ fect the development of AD. Some polymorphisms in genes involved in cholesterol ca‐ tabolism and transport have been associated with an increased level of Aβ and are therefore potential risk factors for the disease. The best known of these genes is apoE4, which is the major genetic risk factor known for late-onset AD. Other genes implicated include cholesterol 24-hydroxylase (Cyp46), the LDL receptor related protein, the choles‐ terol transporter ABCA1, acyl-CoA:cholesterol acetyl transferase, and the LDL receptor. Then, we may conclude that what is bad for the heart is bad for the brain. We must pay attention to risk factors associated with heart disease to prevent Alzheimer's disease also. Considerable interest has also arisen regarding the effects of lifestyle interventions such as exercise and dietary/nutriceutical manipulations.

#### **Acknowledgements**

We dedicate this paper to Dr. Pedro Garzón de la Mora; who was for some of us a guide, and showed us to lose ourselves in the wonderful jungle of Biochemistry.
