Potential Enzymatic Targets in Alzheimer's: A Comprehensive Review

Alzheimer's, a degenerative cause of the brain cells, is called as a progressive neurodegenerative disease and appears to have a heterogeneous etiology with main emphasis on amyloid-cascade and hyperphosphorylated tau-cascade hypotheses, that are directly linked with macromolecules called enzymes such as β- & γ-secretases, colinesterases, transglutaminases, and glycogen synthase kinase (GSK-3), cyclin-dependent kinase (cdk-5), microtubule affinity-regulating kinase (MARK). The catalytic activity of the above enzymes is the result of cognitive deficits, memory impairment and synaptic dysfunction and loss, and ultimately neuronal death. However, some other enzymes also lead to these dysfunctional events when reduced to their normal activities and levels in the brain, such as α- secretase, protein kinase C, phosphatases etc; metabolized to neurotransmitters, enzymes like monoamine oxidase (MAO), catechol-O-methyltransferase (COMT) etc. or these abnormalities can occur when enzymes act by other mechanisms such as phosphodiesterase reduces brain nucleotides (cGMP and cAMP) levels, phospholipase A2: PLA2 is associated with reactive oxygen species (ROS) production etc. On therapeutic fronts, several significant clinical trials are underway by targeting different enzymes for development of new therapeutics to treat Alzheimer's, such as inhibitors for β-secretase, GSK-3, MAO, phosphodiesterase, PLA2, cholinesterases etc, modulators of α- & γ-secretase activities and activators for protein kinase C, sirtuins etc. The last decades have perceived an increasing focus on findings and search for new putative and novel enzymatic targets for Alzheimer's. Here, we review the functions, pathological roles, and worth of almost all the Alzheimer's associated enzymes that address to therapeutic strategies and preventive approaches for treatment of Alzheimer's.