**5. Conclusion**

This review has addressed MS and AD as a strategy to explore the potential relevance of plasma lipoproteins in CNS inflammatory and neurodegenerative disorders. Despite quite different in their demographics, clinical and pathological characteristics, some similarities in their inflammatory and neurodegenerative components have been noted previously [102].

In MS as in AD, the genesis of brain pathology is thought to begin many years before the clinical overt disease. Despite the occurrence of widespread lesions, brain plastic compensatory mechanisms may maintain those disorders clinically silent, delay their symptoms or modify their clinical evolution. Molecular mechanisms underlying grey and white matter plasticity are of outstanding neurobiological and medical importance and are currently poorly understood [111]. This review suggests that an involvement of lipoprotein metabolism in brain plasticity mechanisms is highly plausible and deserves much future research.

Clinical signs of MS very rarely first appear in individuals after 60 years of age and sporadic AD rarely manifest before that age. However, it is remarkable that a profile of low HDLcholesterol, apoE and apoA-I plasma levels and elevated total and non-HDL cholesterol may promote the risk or progression of disability in both disorders. As discussed, this profile could be associated with both the genesis of lesions in the CNS and the systemic immunerelated or metabolic alterations implicated in their pathophysiology (Table 1, Figure 1). It is to note that disturbances in brain cholesterol transport (that may occur in MS, AD and other neuropathologies) can lead to alterations in cholesterol uptake from plasma to brain and decrease plasma HDL levels (112). In MS as in AD, this lipoprotein profile may promote foam cell plaque formations. In young individuals genetically susceptible to MS, this profile may promote the genesis of demyelinating plaques; instead with advanced age, atheroma plaques formation prevails, contributing to AD, in genetically susceptible subjects. Supporting this speculation, MS pathogenesis may share many lipoprotein-related and inflammatory mechanisms underlying atherogenesis (Table1). In addition, with aging, this lipoprotein profile could have a convergent impact for the maintenance of the typical CNS lesions occurring in MS and AD. In fact, advanced ageing may be associated with lower recruitment of anti-inflammatory and phagocytic macrophages and other blood-derived factors to the CNS [113]. This situation, on one hand, favors lower capacity of β-amyloid clearance, oligodendrocyte toxicity and myelin lesions, early present in incipient AD. On the other hand, it restricts remyelination capacities in MS, which are more accentuated with advancing ageing in these patients. The presence of age-related changes in blood circulation has recently been noted of possible relevance for MS and AD [114]. These relevant agerelated changes should comprise circulating lipoprotein metabolism.

Despite the similarities of lipoproteins involvement in these two disorders, including the neuroprotective, immunosuppressive and vascular/ischemic protective functions of HDL-

cholesterol and associated apolipoproteins (Fig. 1), distinctive implications on their pathogenesis are expected. In MS, a participation of lymphocyte infiltration is certainly important while this is not the case for AD. For example, sphingosine-1-phosphate component of HDL could be special relevant for the immune dysfunction and the abnormal sphingosine metabolism associated with the genesis of demyelinating plaques and neurodegenerative processes in MS. In AD, triglyceride-rich plasma lipoproteins and apoE4 isoform are especially relevant in the clearance of Aβ and genesis of amyloid plaques. It should be emphasized that MS and AD are pathological and clinical heterogeneous diseases. For example, the immunopathogenesis of MS differ among patients even with similar clinical profiles and prominent atherosclerosis lesions are absent in some patients with AD. Therefore, the contribution of plasma lipoprotein metabolism for the pathogenesis of these disorders may be variable and this could explain discrepancies among some studies. Future work aimed to clarify the roles of plasma lipoproteins in these diseases should address clinical homogeneous patient populations, include concomitant pathological and immunological markers and consider potential environmental confounders. Ideally, laboratory data should be correlated with neuroimaging measures. Finally, MS and AD are clear examples of complex conditions for which multiple genetic risk factors for developing and progression are to be expected. Selected genetic typing of the study population is therefore convenient, because lipoprotein alterations may not have the same significance and the same therapeutical implications in different genetic backgrounds.

In sum, the available reviewed data suggest that plasma lipoproteins metabolism is a fruitful "window" to an improved understanding of MS and AD and other neurological diseases. Of outstanding interest, plasma lipoproteins may represent useful targets for discovering preventive and therapeutical strategies for these common disabling human conditions.

A very recent paper from Dr Lawrence Steinman group at Stanford University highlights the importance of lipids in the pathogenesis of MS and the therapeutic potential of lipidbased strategies for the disease (Science Transl Med 2012; 8 (137); E-pub 2012 6 Jun).
