Acetylcholine is a neurotransmitter that stimulates cholinergic receptors at chemical synapses in the central nervous system. Patients suffering from Alzheimer's disease (AD) have decreased levels of cholinergic receptors and the most common treatment option is to reduce the breakdown of acetylcholine by inhibiting the enzyme acetylcholinesterase (AChE). 217 Rivastigmine (FDA 2000, Exelon®) and metrifonate (BAY-A-9826, ProMem, 1997) are classified as pseudo-irreversible inhibitors because they react with the critical active site serine residue to form a covalent carbamoyl-AChE complex that temporarily prevents the hydrolysis of acetylcholine in the active site 218 However, metrifonate was abandoned as a treatment for AD because it produces severe muscular and life-threatening respiratory paralysis in some AD patients, a sign of organophosphateinduced delayed neuropathy. Irreversible AChR inhibitors are likely to have selectivity for central nervous system (CNS) because of the reduced rate of resynthesis of CNS AChE. The structural requirements for irreversible AChE inhibitors are thus relaxed; an AChE inhibitor must form an inhibitor-enzyme inactive complex that does not undergo spontaneous hydrolysis. These research findings confirmed the use of methanesulfonyl fluoride (MSF) for the treatment of AD). Sulfonyl fluorides such as MSF, induce AChE inhibition with long-term disease-modifying benefits, perhaps by enhancing acetylcholine-dependent stimulation of neurotrophin nerve growth factor production and release and associated basal forebrain survival processes. C. Tau Tau proteins help to maintain the structure of microtubules in nerve cells. Aggregation of a mutant form of tau is observed in Alzheimer's disease (AD) and may be responsible for some of the observed brain damage. Inhibition of tau aggregation is thus a potential treatment for AD. Among covalent tau aggregation inhibitors (TAIs), oleocanthal, a natural product, reacts with the epsilon amino groups of lysine residues 231, 232 including residues residing in the microtubule binding repeat region, to form imines. In addition, other natural polyphenols are covalent TAIs, such as oleuropein aglycone , abundant in extra virgin olive oil, or green tea-derived (-)-epigallocatechin gallate (EGCG). Other redox-active compounds, including the non-neuroleptic phenothiazine methylene blue (methylthioninium chloride; MTC), can modulate cysteine oxidation when incubated in the absence of exogenous reducing agents. High concentrations of reduced sulfhydryl groups in the form of glutathione normally maintain a reducing intracellular environment 236 , and therefore compounds acting solely through this mechanism could have low potency and efficacy in vivo. In general, covalent mechanisms of tau aggregation inhibition in AD are predicted to have low utility in vivo. However, dimethyl fumarate, an electrophile capable of reacting covalently with cysteine sulfhydryl groups, was approved as an oral treatment for multiple sclerosis 238 , providing further evidence that suggesting that electrophiles acting as covalent inhibitors can be useful therapeutic agents including residues residing in the microtubule binding repeat region to form imines. 239