Alzheimer2

Two other genes linked to early-onset familial Alzheimer Disease are those encoding Presenilin 1 (chromosome 14) and Presenilin 2 (chromosome 1). PS1 and PS2 are structurally similar integral membrane proteins with eight transmembrane domains and are localized mainly in the ER (Endoplasmic Reticulum). PS1 and PS2 are serpentine proteins consisting of 463 and 448 amino acids, respectively. Although both proteins share extensive sequence identity along their entire lengths, their NH2-terminal domains and the second half of their loops are highly divergent, suggesting that these unique regions could modulate different functions of the two presenilins. The role of PS1 in Alzheimer Disease is particularly interesting because it has a strong causal relationship to the disease; mutations for PS1 exhibit 100% penetrance in causing Alzheimer Disease. The presenilin proteins have been shown to play important roles in apoptosis, calcium homeostasis, cell cycle regulation, regulation of misfolded proteins in the ER, and cleavage of APP. The ability ofPS1 to potentiate ABeta toxicity raises the possibility that PS1 interacts with GSK3Beta. The enzyme GSK3Beta also has been implicated in Alzheimer Disease because this kinase is one of a group of proline-directed kinases that can phosphorylate the microtubule-associated protein Tau, to generate a precursor to NFTs, termed paired helical filaments-Tau. PS1 and GSK3Beta can be found in association with NFTs in the Alzheimer brain, which further suggests that there may be a physiological connection between PS1, GSK3Beta, and Tau (Ref.5).

The fourth FAD gene is the ApoE gene, an allele of which (ApoE4) has been associated with increased "risk" for late-onset FAD. Generally three alleles of Apolipoprotein E encode proteins that differ in two amino acids; E2 contains a cysteine in each position, E3 contains a cysteine in one of the positions, and E4 does not contain a cysteine in either position. Individuals with an E4 allele have a reduced life span and are at increased risk of Alzheimer Disease. The mechanism whereby E4 may accelerate brain aging has been suggested to involve a decreased antioxidant and neuroprotective properties of this isoform. ApoE associates with lipoprotein particles and facilitates their interaction with lipoprotein receptors. In neurons, the major ApoE receptor is the LRP (LDL receptor–Related Protein), a large endocytic receptor that regulates proteinase and lipoprotein levels by mediating their catabolism (Ref.6).

Finally, a polymorphism in another LRP ligand, Alpha2M (Alpha2-Macroglobulin), appears to be associated with increased risk for late-onset Alzheimer Disease. Alpha2M is a circulating proteinase inhibitor that can neutralize proteinases from all four classes. In this process, Alpha2M becomes activated to form Alpha2M*, which can be recognized by LRP (Ref.7). Microglia and astrocytes in the brain also play an important role in the development and progression of Alzheimer's disease (AD). Microglia may be activated by oligomeric and fibrillar species of ABeta that are constituents of senile plaques and by molecules derived from degenerated neurons, such as purines and chemokines, which enhance their migration and phagocytosis. The main neurotoxic molecules produced by activated microglia may be reactive oxygen species, glutamate, and inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-alpha) and Interleukin- (IL-1beta) . These molecules differentially induce neurotoxicity (Ref.8 and 9). Activated astrocytes are also capable of accumulating large amounts of ABeta, the later being taken up by astrocytes in association with neuronal debris. In addition, reactive astrocytes seem to accumulate large amounts of neuronal subtype of nicotinic cholinoreceptor (Alpha7nAChRs), which is known to have an exceptionally high affinity to beta-amyloid (Ref.10).

Despite decades of intense research, therapeutics for Alzheimer's disease (AD) are still limited to symptomatic treatments that possess only short-term efficacy. There are currently four main mechanisms of action that are being actively developed in AD therapeutics: Drugs aimed at reducing Abeta production, notably secretase inhibitors; Drugs aimed at reducing Aß plaque burden via inhibition of aggregatio or disruption of aggregates; Drugs aimed at promoting Aßclearance via active or passive immunotherapy; and Drugs aimed at preventing tau protein phosphorylation (Ref.11 and 12).Numerous candidate disease-modifying therapies that target the underlying pathogenic mechanisms of AD are currently in clinical trials. While it is not possible to predict the success of any individual program, one or more are likely to prove effective. Indeed, it seems reasonable to predict that in the not-too-distant futu re, a synergistic combination of agents will have the capacity to alter the neurodegenerative cascade and reduce the global impact of this devastating disease (Ref.13).