Rejuvenating procholinergic treatments for cognition enhancement in AD: current challenges and future prospects.

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by global cognitive decline, with predominant impairments arising in attention and memory (Perry and Hodges, 1999). It is the sixth largest cause of death, and currently there is no way to prevent, cure, or even slow the progression (Klafki et al., 2006; Alzheimer's Association, 2014). Although there is a widespread decline in various neurotransmitter-containing cell bodies and axonal terminals in AD, the most consistent losses are seen in the basal forebrain (BF) cholinergic neurons and its projections (Mesulam, 2004; Schliebs and Arendt, 2011). Because of the documented role of the BF cholinergic system in learning and memory, the “cholinergic hypothesis” of AD was established (Bartus et al., 1982) and has been the primary directive for drug development and treatment in AD for almost three decades. While cholinomimetic drugs such as acetylcholinesterase (AChE) inhibitors, which elevate extracellular levels of the neurotransmitter acetylcholine (ACh), are the viable treatment option for AD and provide moderate alleviation to cognitive impairment, the magnitude of cognitive improvements with these drugs has remained limited (McGleenon et al., 1999; Raina et al., 2008). Additionally, these drugs are not successful in halting the progression of AD. Furthermore, the evidence that non-specific blockade of either muscarinic or nicotinic ACh receptors (mAChRs and nAChRs) alone produce dementia-like symptoms has remained inconsistent (Little et al., 1998; Erskine et al., 2004; Roegge and Levin, 2006). These issues have raised questions concerning the validity of the cholinergic hypothesis and whether the development of procholinergic therapies as cognition enhancers should be considered for AD. Here we argue that psychopharmacological approaches targeting the cholinergic system are based on previous conceptualizations of ACh regulating arousal states. We urge that emerging views from recent studies that refine our understanding of the cholinergic mediation of specific cognitive processes, and how cholinergic mechanisms interact with other pathological markers during the progression of AD, should be considered while designing procholinergic therapies. This discussion will also focus on the development of new drug candidates such as cholinergic receptor subtype-specific agonists, choline transporter (CHT) modulators and neurotrophin-based therapeutics to normalize cholinergic function in AD. Additionally, the need to combine multiple therapeutic approaches to slow AD progression and maximize cognitive benefits will be emphasized.