Recent Developments in Molecular Changes Leading to Alzheimer’s Disease and Novel Therapeutic Approaches

Abstract

Alzheimer’s disease (AD) is a debilitating progressive neurological disease affecting significant number of individuals above the age of 65 years and even those who are as young as 30 years, around the globe. According to the Alzheimer's Association 2011 facts and figures report, Alzheimer’s is the sixth leading cause of death and approximately 5.4 million people age 65 and older suffer from Alzheimer's disease in USA alone. Of all Americans over the age of 65, one out of every eight has AD. As the age advances, the risk of developing AD increases to as much as 47-50% by the age of 85. Risk is even greater if both parents suffer the disease (Bachman et al, 1992). Two types of AD have been described. The sporadic form of AD is a general deterioration of intra-neuronal contact without any association to any genetic element. Familial AD (FAD) on the other hand is associated with mutations in amyloid precursor protein (APP) on chromosome 21 (Goates A.M et al, 1991), apolipoprotein E gene on chromosome 19 (Cedazo-Minguez & Cowburn, 2001), presenilin 1 (PS1) on chromosome 14 (Sudoh et al, 1998), and presenilin 2 (PS2) on chromosome 1 (Jayadev et al, 2010). In addition, high phosphorylation that results in tangle formation is also attributed to mutations in the gene of microtubule associated protein Tau, located on chromosome 17 (Hanger et al, 1992). Among these, deposition of amyloid is widely accepted as the leading cause of AD. Although, amyloid plaque formation was observed in AD brains as early as 1907 (Alzheimer et al, 1995), it was only recently the toxicity (Yankner & Lu, 2009; Yankner et al, 1990) and the contents (Tokutake, 1988; Vital, 1988; Pardridge et al, 1987) have been established. It has been a common observation in several investigations that a single or multiple mutations in any of these proteins alone can affect the performance of other proteins resulting in neurodegeneration. Each mutation in any single protein may differentially affect its function. Therefore, some of the mutations have more drastic consequences than others such as a quintessential mutation in PS2 described by Yu (Yu et al, 2010). In addition some of the mutations appear to cause greater harm than the others by shutting down a whole complex of protein activity such as specific presenilin 1 mutation (Heilig et al, 2010), suggesting that lethality and onset of AD is not a simple process. That said, the converse also appears to be true. That is, if the damage of any one of the affected proteins is reversed, it may be sufficient to alleviate the distress caused by the disease process (Kumar et al, 2000a). In light of the fact that reversal of the changes observed due to