NGF-based cholinergic therapies in Alzheimer disease

The cholinergic system is part of the parasympathetic nervous system, which works in tandem with the sympathetic and enteric nervous systems to maintain the physiologic functioning of our body. The neurotransmitter acetylcholine (ACh) facilitates cholinergic signaling pathways by activating specific cell surface receptors (nicotinic and muscarinic receptors). Altered cholinergic signaling has been implicated in several pathologic conditions. In this chapter, conditions where cholinergic modulation in the central nervous system occurs through the neurotrophin nerve growth factor (NGF) are addressed. NGF is the master regulator of several pathways, ultimately leading to cell survival, ACh production, regenerative signaling, and anti-inflammatory tone. NGF and cholinergic-related pathways have been reported to be severely affected in the case of Alzheimer disease (AD), the most common dementia disorder. In AD, the cholinergic nuclei of the basal forebrain are affected early during the AD continuum, resulting in cholinergic cell loss and hampered ACh production, which overall affects the propagation of cholinergic signals in other brain regions. Since the 1990s clinically relevant strategies to treat AD patients have been the drugs that enhance cholinergic signaling-termed cholinesterase inhibitors (ChEIs), however, other strategies in AD have been and are presently being assessed for clinical efficacy. Delivery of NGF to the basal forebrain is considered crucial to revive the cholinergic cell bodies, restore ACh production, and sustain cognitive function. This chapter provides a description of the relevance of NGF-based therapies targeted for AD treatment, technical approaches for NGF delivery to the brain, and the status of ongoing clinical studies are provided.