**4.2 Role of polyunsaturated fatty acids (PUFAs)**

PUFAs and their oxylipins may affect the onset of AD [14]. The administration of omega-3 fatty acids may cause a dose-dependent reduction of triglyceridemia and cholesterolemia and exert an antiatherogenic effect [15]. With regard to mechanisms, in view of the proposed protective role of unsaturated fatty acids in phospholipids against the free radical-mediated injury of membrane proteins [9], it should be mentioned that the distribution of unsaturation (the trap for unpaired electrons) across the membrane leaflets is not uniform, and minima (the least protected areas from oxidative stress) were observed close to the C-6 site (i.e., very close to the membrane exterior, to the phosphorylable site of HMGCoAR, and to the vulnerable site of APP) and at the C-15 and C-17 levels (closer to the free radical conductor dolichol) [16]. Quite interestingly, signal might help focus free radicalmediated injury on the right target; more interestingly, in ad-libitum-fed (shorterlived) rats, is its recognizability that may fade on aging: the abundancy of double bonds near the C-6 site (but not at the C-15 and C-17) indeed appears to increase up to a doubling by age 24 months. Furthermore, this age-related change is prevented in part by nutritional anti-aging intervention [17]. Perhaps age-related changes in the production of Aβ1-42, in the activity of HMGCoA reductase, and in the PUFA content of membrane phospholipids are all somehow bound together and involved all in the risk of AD. As an additional comment, beneficial intervention on Aβ1-42 production may require the administration of antioxidants (e.g., polyphenols and resveratrol) to curb oxidative stress and of omega-3 fatty acids at a high dosage at the first good meal after fast (on the anabolic phase of metabolism) to counteract age-related changes in phospholipid unsaturated fatty acids and increase membrane

**23**

*Primary Prevention of Alzheimer's Disease (AD) DOI: http://dx.doi.org/10.5772/intechopen.85418*

autophagy) [18].

nal death [23].

**6. AD-associated changes in cholesterol metabolism**

Abnormal cholesterol metabolism is an established feature of AD: levels of cholesterol are increased in MCI subjects and levels of 24-hydroxycholesterol and 27-hydroxycholesterol are elevated compared to controls both in AD and MCI subjects [24]. It appears that the rate of cholesterol production may be boosted by a free radical attack via a constitutive activation of HMGCoA-reductase, the rate-limiting step in sterol biosynthesis. Mechanism was clarified by Bergamini group in Pisa in cooperation with Trentalance group in Rome: in the rat, a free radical attack may prevent AMP-dependent protein kinase from phosphorylating a serine residue close to the C-terminus of HMGCoA reductase, Ser 872 with human enzyme [25, 26]. It has been proposed by several authors that higher cholesterol may disturb the lipid raft domains in various membrane organelles and affect the functioning of α, β, and γ secretases as well as APP itself and the production of Aβ 42; and that by converse, the toxicity of Aβ may be produced, in part, by disturbing the composition of the lipid raft domains in which they reside [27, 28]. Both with in vitro experiments and with animal models, statins strongly lowered blood cholesterol and reduced the levels of Aβ peptides, Aβ 42 and A β40 [29, 30]. However, a statistically significant correlation between two events does not necessarily imply the existence of a causal link: an alternative explanation is that the events share a common cause. This might

**5. The pathogenesis of AD**

resistance to oxidative stress. An enhancement of the membrane turnover rate may be useful (e.g., by dietary restriction and/or pharmacological stimulation of

The hypothesis of the amyloid cascade attributes to beta-amyloid, the responsibility of all cases of AD, and considers the tau pathology and other degenerative changes secondary to the Aβ pathology. Indeed, the extracellular accumulation of Aβ, a hallmark of AD, produces ROS, including hydrogen peroxide (H2O2) in the presence of Fe3+or Cu2+ [19, 20]. The amyloid β-peptide responsible for AD is generated within the transmembrane domain (TMD) of a C-terminal fragment of the amyloid β protein-precursor (APP CTFβ) by the proteolytic action of the γ-secretase complex [21]. Very interestingly, it was shown that some mutation(s) that promote destabilization of TMD helix might affect the length of the accumulated Aβ species and the ratio of the toxic Aβ42 to the safer Aβ40 peptide and may result in a young-onset AD [22]. Hence, the speculation may be invited that a free radical-induced modification in (some) amino acids of APP close to the C-6 carbon of phospholipid fatty acids might have a similar effect and enhance amyloid deposition. With regard to disease progression, many different active factors in sequence would determine timing of neuronal damage and symptom development, such as: (1) an overproduction of the toxic Aβ peptide (1-42) for genetic reasons and/or decrease in the quality of the antioxidant device of the membranes, (2) an ensuing increase in Aβ excretion in the oligomeric form may concentrate the redoxactive copper at neuronal membranes before stacking in amyloid fibrils to form an ROS generating complex, (3) oxidative stress may be enhanced with an ensuing increase in lipid peroxidation and di-tyrosine formation, and (4) inflammation and activation of the microglia, which may further increase free radical generation, spread lytic enzymes, and cause cytotoxicity and anticipation of apoptotic neuroresistance to oxidative stress. An enhancement of the membrane turnover rate may be useful (e.g., by dietary restriction and/or pharmacological stimulation of autophagy) [18].
