Alternative Pharmacological Strategies for the Treatment of Alzheimer’s Disease: Focus on Neuromodulator Function

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder, comprising 70% of dementia diagnoses worldwide and affecting 1 in 9 people over the age of 65. However, the majority of its treatments, which predominantly target the cholinergic system, remain insufficient at reversing pathology and act simply to slow the inevitable progression of the disease. The most recent neurotransmitter-targeting drug for AD was approved in 2003, strongly suggesting that targeting neurotransmitter systems alone is unlikely to be sufficient, and that research into alternate treatment avenues is urgently required. Neuromodulators are substances released by neurons which influence neurotransmitter release and signal transmission across synapses. Neuromodulators including neuropeptides, hormones, neurotrophins, ATP and metal ions display altered function in AD, which underlies aberrant neuronal activity and pathology. However, research into how the manipulation of neuromodulators may be useful in the treatment of AD is relatively understudied. Combining neuromodulator targeting with more novel methods of drug delivery, such as the use of multi-targeted directed ligands, combinatorial drugs and encapsulated nanoparticle delivery systems, may help to overcome limitations of conventional treatments. These include difficulty crossing the blood-brain-barrier and the exertion of effects on a single target only. This review aims to highlight the ways in which neuromodulator functions are altered in AD and investigate how future therapies targeting such substances, which act upstream to classical neurotransmitter systems, may be of potential therapeutic benefit in the sustained search for more effective treatments.

Mapping the bioimaging marker of Alzheimer’s disease based on pupillary light response-driven brain-wide fMRI in awake mice

“…Multiple neuronal sources drive the highly varied pupil dynamics, including pupillary light responses (PLR), through autonomic neuromodulation to control pupil dilation and constriction [9][10][11][29][30][31][32][33][34][35][36] . Since neuromodulatory dysfunction is often observed in degenerative AD brains [37][38][39][40] , it is plausible to identify dynamic PLR serving as novel functional biomarkers based on converging effects from malfunctional neuromodulatory pathways of AD brains. The ongoing challenge is to bridge the complex PLR with the underlying brain-wide functional alteration in degenerative AD brains.…”