Despite recent leaps in modern medicine, progress in the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents the entry of therapeutics into the brain, and the complexity of neurological processes, limits the specificity of potential therapeutics. Moreover, a lack of etiological understanding and the irreversible nature of neurological conditions have resulted in low tolerability and high failure rates towards existing small molecule-based treatments. Neuropeptides, which are small proteinaceous molecules produced by the body, either in the nervous system or the peripheral organs, modulate neurological function. Although peptide-based therapeutics originated from the treatment of metabolic diseases in the 1920s, the adoption and development of peptide drugs for neurological conditions are relatively recent. In this review, we examine the natural roles of neuropeptides in the modulation of neurological function and the development of neurological disorders. Furthermore, we highlight the potential of these proteinaceous molecules in filling gaps in current therapeutics.

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.

Executive dysfunction encompasses altered decision-making, attentional deficits, excessive risk-taking behaviours, and inefficient planning. Alongside memory loss, these cognitive deficits are amongst the most frequently reported symptoms of Alzheimer’s disease (AD). Normal executive function depends on connectivity between the ventral hippocampus and medial prefrontal cortex (mPFC), yet abnormalities in this circuit and how such changes lead to cognitive dysfunction in AD have yet to be fully elucidated. Here, we show that 6-month-old male 3xTg AD mice display maladaptive decision-making in the rodent 4-Choice Gambling Task measure of executive function. Extracellular field recordings in the infralimbic cortex of age-matched 3xTg mice show layer-specific reductions in response amplitude and paired-pulse ratio compared to controls following activation of hippocampal input fibres, indicating changes to short-term hippocampal-prefrontal synaptic plasticity. These results therefore reveal a pre-clinical deficit in executive function that correlates with mPFC synaptic plasticity deficits in a mouse model for AD.

Executive function depends on connectivity between the ventral hippocampus and medial prefrontal cortex (mPFC). How abnormalities in this pathway lead to cognitive dysfunction in Alzheimer’s disease (AD) have yet to be elucidated. Here, male 3xTg AD mice at 6-months displayed maladaptive decision-making in the rodent 4-Choice Gambling Task measure of executive function. Extracellular field recordings in the infralimbic cortex at this age showed layer-specific reductions in response amplitude and paired-pulse ratio following activation of hippocampal input fibres, indicating changes to short-term hippocampal-prefrontal synaptic plasticity. Bulk RNA sequencing of the mPFC in 6-month-old mice identified differential gene expression changes associated with calcium ion transport, glutamatergic, GABAergic, and dopaminergic neurotransmission. Seven of these genes ( Gpm6b, Slc38a5, Ccr5, Kcnj10, Ddah1, Gad1, Slc17a8 ) were also differentially expressed in 3-month mice. These results reveal a pre-clinical deficit in executive function correlating with synaptic plasticity and gene expression changes in the mPFC of male 3xTg mice.

Executive function depends on connectivity between the ventral hippocampus and medial prefrontal cortex (mPFC). How abnormalities in this pathway lead to cognitive dysfunction in Alzheimer’s disease (AD) have yet to be elucidated. Here, male 3xTg AD mice at 6-months displayed maladaptive decision-making in the rodent 4-Choice Gambling Task measure of executive function. Extracellular field recordings in the infralimbic cortex at this age showed layer-specific reductions in response amplitude and paired-pulse ratio following activation of hippocampal input fibres, indicating changes to short-term hippocampal-prefrontal synaptic plasticity. Bulk RNA sequencing of the mPFC in 6-month-old mice identified differential gene expression changes associated with calcium ion transport, glutamatergic, GABAergic, and dopaminergic neurotransmission. Seven of these genes (Gpm6b, Slc38a5, Ccr5, Kcnj10, Ddah1, Gad1, Slc17a8) were also differentially expressed in 3-month mice. These results reveal a pre-clinical deficit in executive function correlating with synaptic plasticity and gene expression changes in the mPFC of male 3xTg mice.