Alzheimer disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. Mutations in some of the components of the amyloid pathway, such as the amyloid precursor protein (APP), ApoE, Presenilin-1 and PS2 (PS1, and Presenilin-2) and SORL1 are responsible for autosomal-dominant early-onset familial Alzheimer disease (FAD) (Ref.1). Alzheimer s disease is the most common cause of dementia among the elderly. With the advent of the aging society (Ref.2)
The APP is synthesized and transferred to the plasma membrane where it is processed by either the non-amyloidogenic or amyloidogenic pathways. In the non-amyloidogenic pathway, APP is processed without giving rise to the deleterious beta amyloids. However, in the amyloidogenic pathway, APP is internalized and ends up in the late endosomes where it is hydrolysed by beta-secretase (also known as BACE) that sheds the N-terminal sAPPbeta region leaving the C-terminal fragment beta (CTF beta) in the membrane. This CTF beta is hydrolysed by the gamma-secretase complex that contains the presenilin enzymes, either the PS1 or PS2 isoforms. This gamma-secretase cleaves CTF beta at two sites to yield either amyloid beta 40 (Abeta40) or amyloid beta 42 (Abeta42), which are then released to the inside of the vesicle, and the APP intracellular domain (AICD) that is released to the cytoplasm. The amyloids are transported and released to the surface via the constitutive secretory pathway (Ref.1). Since all known genetic risk factors for Alzheimer Disease impact ABeta metabolism, it is believed that the accumulation of ABeta fibrils into amyloid plaques plays a key role in the onset and/or progression of the disease. As ABeta peptide aggregates, it generates ROS (Reactive Oxygen Species). ABeta generates Reactive Oxygen Species (hydrogen peroxide and hydroxyl radical) by a mechanism that may involve metal-catalyzed oxidation of methionine. When this process occurs in the immediate vicinity of cell membranes, lipid peroxidation is initiated. ABeta induces membrane lipid peroxidation, which results in impairment of the function of membrane glucose and glutamate transporters, altered mitochondrial function, and a deficit in ATP levels; 4-HNE (4-hydroxynonenal) appears to be a mediator of these actions of ABeta. Oxidative stress induced by ABeta may be particularly detrimental for neuronal function and survival when it occurs in synapses. Cumulative ROS-induced membrane damage compromises membrane integrity and increases the permeability of several ions, including calcium; resultant calcium influx is a crucial factor in neurodegeneration. Calcium influx, moreover, promotes recruitment of other ion channels and generation of additional ROS, resulting in neuronal excitotoxicity. Importantly, ROS accumulation fosters calcium influx, which, in turn, fosters yet further ROS accumulation. Calcium influx initiates neurodegeneration in Alzheimer Disease. MAP kinase mediates multiple aspects of ABeta -induced neurotoxicity. MAP kinase may not directly phosphorylate Tau but instead may, by activating the L voltage sensitive calcium channel, foster Tau phosphorylation by other calcium-dependent kinases. Notably, the intracellular Tau kinases, calcium-Calmodulin Kinase and PKC (Protein Kinase C), are both calcium-dependent. In addition, prior phosphorylation of Tau by CamK or PKC facilitates subsequent phosphorylation by GSK3Beta (Glycogen Synthase Kinase-3-Beta). Thus, altered calcium homeostasis is a convergence point of various aetiological factors relevant to the pathogenesis of Alzheimer's disease. In particular, loss of calcium homeostasis has been implicated in causing Tau hyperphosphorylation and neuronal apoptosis (Ref.3). CDK5 (Cyclin-Dependent Kinase-5) may be one of the kinases 'activated' by ABeta peptide through Calpain-mediated conversion of p35 to p25. CDK5 and its neuron-specific activator p35 are required for neurite outgrowth and cortical lamination. Proteolytic cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease. Under neurotoxic conditions, p35 is proteolytically cleaved by Calpain to produce p25. Generation of p25 results in degeneration of CDK5. Consequently, the p25/ CDK5 kinase hyperphosphorylates Tau,disrupts the cytoskeleton and promotes the death (apoptosis) of primary neurons. Cleavage of p35 to p25 by Calpain, suggests one mechanism by which calcium can activate a Tau phosphorylating kinase (Ref.4).
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 of PS1 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 Aß clearance 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).