• Maintenance of biophysical membrane properties
• Maintenance of a membrane potential in neurons
• Regulation of synaptic membrane composition
• Maintenance of synaptic transmission
• Control of the metabolism of both APP and tau protein b-amyloid deposits as a hallmark of AD tell us they are important. However, in contrast to familial AD, it has to be proven yet that the mismetabolism of APP and the increased formation of the derivative b amyloid contribute to the generation of sporadic AD. Recent evidence has been provided that an ► insulin resistant brain state (► IRBS) may play a pivotal role in the generation of the latter dementia form (Grunblatt et al. 2007; Riederer and Hoyer 2006; Salkovic-Petrisic et al. 2006). Several age-related candidates may contribute to the causation of an IRBS:
• Increased concentration of cortisol that may cause neuronal insulin receptor desensitization by inhibition of its tyrosine residues phosphorylation
• Increased activity and metabolism of noradrenaline and increased concentration of cAMP that lead to the decrease of the receptor's tyrosine kinase activity
• Increased concentration of ROS (the uncharged species hydrogen peroxide) that may persistently inhibit the activity of phosphotyrosine phosphatase, thus inhibiting its dephosphorylation and rendering the insulin receptor ineffective
• Increased concentration of long-chain fatty acids that may reduce insulin's receptor binding
An IRBS may induce diverse abnormalities in cellular and molecular brain metabolism (Hoyer 2004) (Fig. 1), among which is the reduction of glucose metabolism including the compound F-6-P, acetyl-CoA, and ATP. F-6-P decrease favors tau hyperphosphorylation; the fall of acetyl-CoA diminishes the formation of both acetyl-choline and cholesterol. The reduction of the former decreases the cellular release of APP via its muscarinic receptors; likewise, learning, memory, and cognitive capacities decline. The reduction of cholesterol in the cell membrane changes its properties and may, thus, damage receptor function. The deficit in ATP has a cascade-like effect on diverse ATP-dependent cellular and molecular processes (see above) which may damage cell functions and may jeopardize the survival of the cell. The compromised insulin signaling downstream of the insulin receptor may activate glycogen synthase kinase-3a/p which may result in hyperphosphorylated tau protein and increased production of b-amyloid (Hoyer 2004). The reduced insulin signal may downregulate IDE resulting in a reduced capacity to degrade b-amyloid and, thus, favoring its cellular accumulation.
In contrast to the hereditary form of AD, sporadic AD may be considered to be a complex and self-propagating metabolic brain disease showing predominating abnormalities in oxidative/energy metabolism including decreases in the formation of both acetylcholine and cholesterol finally ending in the formation of neuritic plaques and neurofibrillary tangles. Therefore, a "rational" therapy may be based upon different strategies.
Neurodegeneration and Its Prevention. Fig. 1. Candidates which may induce an insulin resistant brain state (IRBS) and a survey of diverse effects thereafter.
According to all available information about the pathology of sporadic AD, it is evident that multiple drug regimes are necessary in order to come closer to a "disease modifying'' treatment strategy. Therefore, multifunctional drugs are necessary to be developed. While the development of anti-Alzheimer (dementia) drugs involves all currently known pathological principles driven by globally acting industry as well as smaller companies and start-up companies, the concept of developing multifunctional drugs is still the one followed by relatively few (Riederer and Gerlach 2009). Worldwide enormous capacity focuses developments into (1) new substances to inhibit acetylcholine esterase or to block glutamatergic N-methyl-D-aspartate (NMDA) receptor subunits. Currently, several drug companies develop novel compounds as ► acetylcho-line esterase inhibitors and also various types of glutama-tergic receptor antagonists (Riederer and Gerlach 2009). Other strategies are related to nicotinergic and muscar-inergic receptor subtype modulation (see Ragozzine; this volume). These are not expected to be ► disease-modifying strategies. The therapeutic potency, side effects, and adverse reaction profile of receptor subtype specific nicotinic and muscarinic drugs still have to be evaluated. (2) There is profound knowledge about the b-amyloid pathology. Based on this, many companies try to develop (1) protein aggregation inhibitors, (2) band g-secretase inhibitors, or (3) vaccination strategies against Ab-induced plaques (see Le Sage and Pentel; this volume). For the latter, caution is suggested if the data from Holmes et al. (2008) are taken into consideration. These postmortem human brain studies performed on AD patients who have deceased after vaccination with AN 1792 give evidence that reduction of plaque load is not correlated with any cognitive improvement. However, it has been suggested that vaccination at progressed stages of AD comes too late. Therefore, early vaccination strategies are envisaged.
Much less efforts are taken into the reduction of tauprotein related pathology. The reason might be that the focus has been on amyloid because of the proven genetic link between AD and amyloid in the admittedly small number of familiar AD cases.
Current pharmacotherapeutic strategies of sporadic AD consist of supplementation of central acetylcholine deficit by acetylcholine esterase inhibitors (see Newhouse; this volume) and by an ► NMDA receptor antagonist. In addition to this standard therapy, other options for interfering with pathological mechanisms are antioxidants to defeat the action of ROS (vitamins-A, -E and -C or Ginkgo biloba). All these therapeutic interventions together are suitable to improve the ► quality of life of AD
patients for about 1-2 years, but they are unable to reduce or even halt the progression of this devastating disorder.
Antioxidative drug developments are of more general interest as oxidative stress is proven in all neurodegenera-tive disorders. The same holds true for anti-inflammatory drug developments.
One aspect that, at least in our minds (see above), deserves more attention is influencing the "glucose metabolism." Drug-related interactions are given by (1) a-and b- (PPAR) g-agonists, (2) glycogen synthase kinase (GSK)-3-a and -b-inhibitors, as well as (3) inhibitors of advanced-glycation-end (AGE) product biosynthesis or inhibitors of AGE-receptors. It is to hope that part of such research will come from antidiabetic research and respective drug developments. Influencing the "IRBS" is right now the most plausible mode of action to causally treat sporadic AD (Griinblatt et al. 2007; Riederer and Hoyer 2006; Salkovic-Petrisic et al. 2006).
There is still a debate about cholesterol, hypercholes-terolemia (as measured in plasma/serum), and the use of antihypercholesterolemia directed drugs, statins. As we have pointed out earlier (Hoyer and Riederer 2007) it is necessary to distinguish between the peripheral and central cholesterol-related pathology. There is no question that the treatment of peripheral hypercholesterolemia is useful to reduce and avoid, for example, cardiovascular disturbances. Chronic increase of plasma/serum cholesterol may also disturb the functioning of brain capillaries and thus may provoke b-amyloid pathology within the capillaries epithelium. If so, "peripheral" antihypercho-lesterolemia treatment by peripherally acting statins may be useful. Experimental proof for this working hypothesis, is, however, still lacking.
As peripheral cholesterol does not pass the ► blood-brain barrier, knowledge about soluble and membrane-bound cholesterol in brain regions involved in the pathology of sporadic AD is speculative. While there is evidence for (1) reduced cholesterol in membranes undergoing degeneration and (2) disturbed membrane fluidity based on an imbalance of the cholesterol/fatty acid ratio, there is no data available to judge the role of soluble neuronal/extraneuronal cholesterol. In case of such lack of knowledge, it is not justified to use centrally acting statins, as they may lead to worsening of AD if used in a chronic treatment design. In line with this are all the negative outcomes of prospective clinical studies using statins for sporadic AD (Hoyer and Riederer 2007).
However, all pharmacotherapeutic actions are too late to be effective as "disease-modifying" or even neuroprotective or neurorestorative strategy (see Rhodes and Green; this volume). Therefore, development of biomarkers in
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