Alzheimer's amyloid beta and lipid metabolism: a missing link?

THE EXCELLENT ARTICLE by Baggio et al. was of particular interest to us because it addressed an important issue pertaining to our special subject of Alzheimer’s research: the ‘‘hypothesis that a continuous reshaping in lipid physiology occurs with age and is a critical factor for survival and successful aging. ’’ (1) The authors are correct that ‘‘changes in the serum level of protein, lipids, and lipoproteins that are considered risk factors for atherosclerotic vascular diseases in young people may lose their biological significance and assume a different, unknown role with advanced age. ’’ But we are beginning to learn that blood lipids are indeed associated with Alzheimer’s disease (AD) and our group and others are discovering that Alzheimer’s may be very closely linked to human lipid metabolism change. First, it has been shown (2) that the lecithin cholesterol acyl transferase (LCAT) activity is significantly decreased in Alzheimer’s patients. LCAT catalyzes an acyltransferase reaction that forms most of the cholesterol esters and is a key step in reverse cholesterol transport in humans. This makes the enzyme of obvious significance in the development of atherosclerosis and heart disease. Moreover, as was demonstrated a decade ago (3), this is also the case with Down’s syndrome (DS), where there are the same blood changes in LCAT activity. This indicates that changes in this enzyme are related to the etiologies of both AD and DS on the one hand and vascular pathology on the other. In addition, there is a remarkable resistance to systemic atherosclerosis in DS (4), which is not yet shown in AD. Second, it has been proposed (5) that membrane destabilization in Alzheimer’s disease as a natural consequence of primary defective lipid composition (5) is important in the membrane damage that leads to brain cell death. The membrane destabilization was found to occur selectively at the areas of neurodegeneration in AD brain, thus potentially accounting for the localized lipid pathology. Our own research activities are focused on understanding in more detail the normal biology of Alzheimer’s amyloid beta protein (Ab). This small protein has a high tendency to form insoluble amyloid aggregates. Amyloid deposition of cerebrovascular amyloid and senile plaques is a characteristic feature of the Alzheimer’s brain and the latter was reported to occur in the brain of heart disease patients (6, 7). Nevertheless, in 1992 it became clear that Ab is not just a pathological protein. At that time several research groups (8–10) detected it in a ‘normal’, soluble (sAb), nonaggregated state in blood and cerebrospinal fluid (CSF) of both normal people and patients with AD. The question why this protein does not aggregate normally became of special interest to many Alzheimer’s research teams. Published data regarding Ab binding to a number of proteins, and in particular to apolipoproteins in a test tube (11, 12), led us to a hypothesis that these interactions reflect an sAb association with lipoproteins, of which apolipoproteins are protein constituents. Evidence described in our recently published papers (13–15) indicates an association of sAb with special class of normal blood and CSF lipoproteins, high density lipoproteins (HDL), believed to be a protective factor in atherosclerotic vascular disease. Furthermore, sAb is secreted by hepatic cells as a part of lipoprotein complex (16). Association of Alzheimer’s amyloid beta with HDL suggests a mechanism for maintaining it in normal soluble, not aggregated state in blood and body fluids of normal individuals (13–15). Moreover, HDL carry LCAT, the key enzyme of cholesterol removal from the body, activity that in the disease is changed (see above). On the basis of the observations described above, we tested the effect of Ab on cholesterol esterification