ALZHEIMER'S DISEASE (AD)

"Sticky" (or poorly water-soluble) protein fragments such as those derived from the amyloid precursor protein may require special disposal or transport pathways for their clearance from cell compartments and tissues. Current evidence suggests that major ("neurodegenerative") diseases of the brain including Alzheimer's, Huntington's, and Parkinson's disease are related to the accumulation inside (and outside) of brain cells of poorly soluble protein fragments. Generally, it appears that in these diseases different proteins (chains of amino acids) may enter abnormal pathways because they curl up inside of the cells the wrong way (theory of protein misfolding, reviewed in Neurobiology of Aging, volume 23, pages 957-976, 2002).

Amyloid precursor protein (APP) normally exists as a transmembrane protein. Such proteins have special segments (amino acid chains curled up into spirals, so-called alpha helices) that traverse the oily medium of cell membranes, whereas segments of the protein that stick out inside and outside of the cells are water-soluble, existing in cell water and extracellular water. Transmembrane proteins might be likened to an arrow piercing a target carpet (corresponding to cell membrane) with only the front part of the arrow emerging on the backside of the carpet. Transmembrane proteins often contribute to cell-to-cell communication, acting as membrane receptors transmitting ( "transducing") molecular signals across cell membranes. Therefore, the normal function of amyloid protein inserted in the cell membrane of brain nerve cells may be that of a cell surface receptor, but details of this putative receptor function remain unclear. Cell membranes contain regionally different fats (lipids) to form a lipid mosaic. Importantly, transmembrane proteins with receptor function may have a proclivity to stabilize in parts of the membrane mosaic rich in cholesterol and another fat (sphingolipid). These cholesterol-rich membrane regions accommodating transmembrane proteins are less liquid than the rest of the cell membrane and are called "lipid rafts". Lipid rafts may be likened to miniscule platforms of butter surrounded by a film of less viscous olive oil. It has been recently suggested that amyloid precursor protein existing in lipid rafts becomes particularly susceptible to degradation by beta and gamma secretases to produce fragments (beta amyloids) likely to form harmful aggregates (amyloid plaques) (Journal of Cell Biology 2003, vol. 160, pages 1123-123). Proteins in lipid rafts may be sequestered or internalized into cells via a mechanism that involves the internal "pinching off" of small patches of cholesterol-rich membrane carrying the protein (so-called endocytosis). There is evidence from cell-culture studies that endocytosis-related disposal of amyloid proteins invites their aggregation, the process underlying amyloid plaque formation. Experimental removal of cholesterol from the cell membranes inhibits APP processing associated with beta amyloid aggregation.

In brief, high brain cholesterol levels may favor cholesterol-related alterations in cell membrane function and lead to the type of amyloid precursor protein processing that promotes protein fragment-induced nerve cell damage and Alzheimer's disease. Several clinical and experimental observations support this conclusion:

1. Population studies indicate that individuals with high ("bad") blood cholesterol levels in mid-life have an increased risk of developing Alzheimer's disease in late life.
2. Large-scale retrospective population studies reveal that persons in the upper 20% for estimated fat intake have more than double (2.2 times) the risk of developing Alzheimer's disease compared with persons in the lowest 20% (Achives of Neurology 2003; vol 60, pages 194-200).
3. In two retrospective population studies (Lancet 2000; vol.356, pages 1627-1631,; Archives of Neurology 2000; vol. 57, pages1439-14343,), treatment with drugs that lower bad blood cholesterol (so-called statins such as atorvastatin [=Lipitor®], pravastatin [Pravachol®), symvastatin [=Zocor®] ], rosuvastatin [=Crestor®]) was associated with decreased risk of developing Alzheimer's.
4. Genetically determined variants of cholesterol transport in brain increase the risk of Alzheimer's disease. The proteins involved are those contributing to so-called reverse cholesterol transport, i.e., export or efflux of cholesterol from non-liver cells towards the liver, the only organ capable of freeing the body from excess cholesterol. The most conclusive linkage between a protein regulating cholesterol efflux and Alzheimer's is the cholesterol carrier apolipoprotein E (ApoE). Individuals with a variant ApoE (ApoE4) that limits cholesterol efflux from nerve cells have an increased risk for developing Alzheimer's disease. Additional proteins acting as Alzheimer risk factors are ineffective variants of the ABCA1 transporter (first step in activating export or efflux of cholesterol across cell membranes) and brain-specific CHYP46 (an enzyme converting cholesterol into 24-hydroxy-cholesterol, a chemical modification facilitating elimination of cholesterol from the brain compartment). Thus, specific variants of cholesterol transport-regulating genes occurring in multiple variants in the general population (so-called polymorphism) determine a person's risk of developing Alzheimer's disease. However, gene variants (alleles) thus far recognized do not act as strong disease predictors. In the case of ApoE, only 12-18% of all Alzheimer's cases can be related to the ApoE4 allele, and the early or late onset of the disease is ApoE4-related in only 4-9% of all cases.
5. Genetically modified mice (transgenic animals) expressing human amyloid precursor protein develop an increased brain amyloid plaque load in the presence of dietary or genetic elevations in blood cholesterol.

These findings appear to support a relation between the regulation of brain cholesterol and Alzheimer type dementia. However, it is difficult to rule out the possibility that alterations of cholesterol regulation act also indirectly by adversely altering small brain blood vessels and creating brain damage from insufficient brain blood flow (see above, paragraph on disease of small brain blood vessels).

The distinction between cerebrovascular dementia and Alzheimer's dementia is partly a false problem. Ever since Alzheimer described his two initial patients, pathologists recognized that patients with dementia exhibited in addition to nerve cell changes almost always (in some studies in 98% of cases) abnormalities of the brain vessels. As already mentioned above, one abnormality affecting small brain arteries is known as "cerebral amyloid angiopathy" (often abbreviated as CAA). In this disease, beta amyloid protein is detected in association with membranes of all types of cells occurring in arterial (or capillary) walls, namely endothelial cells, smooth muscle cells, and pericytes. The vessel wall deposits may be massive and ultimately obliterate wall structure ("hyalinosis"). Such changes impair vessel permeability and may invite brain-damaging hemorrhages. The origin of the amyloid deposits in vessel walls is disputed. Some authors propose that amyloid in small vessel walls represents nerve-cell amyloid that has been held up during its drainage by the blood vessels (clearance-related accumulation). However, beta amyloid accumulating in vessel walls may differ slightly from that generated by brain nerve cells. Further, genetic studies demonstrate that beta amyloid precursor protein (APP) is produced (expressed) not only by brain nerve cells, but also by the cells lining the inner surface of blood vessels (endothelial cells). Important, APP production in brain nerve cells and arterial cells may be regulated by the same stimulatory (circulating) factors. Vessel walls damaged by a variety of insults (infections, immune responses, heat or cold injury) are known to become susceptible to injury by high circulating cholesterol levels (bad cholesterol or LDL levels). Therefore, amyloid-related vessel disease is almost certainly a mechanism inviting and aggravating cholesterol-induced vessel disease (atherosclerosis). Conversely, as delineated above, elimination of beta amyloid fragments from nerve cells may critically depend upon cholesterol dependent clearance mechanisms (endocytosis and others).

In brief, recent insights into mechanisms that promote beta amyloid- and cholesterol- related cell injury at the level of brain cells and cells of the vessel walls suggest strongly interdependent and interactive processes. Therefore, attempts to dissociate amyloid-related disease of brain nerve cells from that of vessel cells appears almost a futile endeavor. This partly explains that identical therapies such as cholesterol-lowering interventions with diet and statins may beneficially influence both atherosclerosis (cholesterol-related vessel disease) and Alzheimer's dementia. Current scientific evidence strongly supports the recommendation to adhere to low cholesterol diets (low animal fat diet) that protect against coronary disease, stroke, and in all probability senile dementia.

The experimental and clinical evidence that amyloid precursor protein (APP) is involved in causing dementia of the Alzheimer type is nearly overwhelming. In the amyloid cascade hypothesis it is assumed that processing of APP into beta amyloids (Ab's) and aggregation of these fragments are directly or indirectly injurious to nerve cells. This hypothesis is for instance supported by immunotherapy in which vaccination-induced antibodies that somehow neutralize amyloid fragments by binding to them, appear to retard experimental Alzheimer syndromes. Although the amyloid cascade hypothesis provides a most useful framework to account for many experimental and clinical findings and for mounting exciting therapeutic strategies, numerous observations remain unexplained. Above, we mentioned that APP's normal function may be that of a receptor for signal transmission across nerve cell membranes. It is possible that abnormalities in the function of APP in membranes is the primary disease-producing event and that amyloid aggregation is merely a downstream manifestation of the primary disturbance (Brain Research 2000; vol. 886, pages54-56). It is however most important to recognize that upstream and downstream mechanisms are not mutually exclusive and might both be operative in causing nerve cell damage. Atherosclerosis research has provided an instructive example how a single simple molecule - cholesterol - may exert multiple injurious effects along its biochemical pathways: 1) precursors of cholesterol synthesis (isoprenoids) may affect cell signaling to imbalance inflammatory responses; 2) cholesterol, carried by proteins (apoproteins) or accumulating as free cholesterol in cells, may directly adversely affect cell function; and 3) cholesterol derivatives (so-called oxysterols) may be independently injurious. The multi-level effects of cholesterol are in fact highly pertinent to our context, since they provide alternate hypotheses how to link cholesterol metabolism to Alzheimer's disease. This cannot be discussed in detail here.