Neuroregeneration Versus Neurodegeneration: Toward a Paradigm Shift in Alzheimer'S Disease Drug Discovery

Abstract

Alzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clinical trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small molecules have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biology. Classically, these molecules have been generated either by target-based or phenotypic approaches. To circumvent specific liabilities, nanomedicines emerge as a feasible alternative. However, this review is not intended to be comprehensive. Its purpose is to focus on recent examples that could accelerate development of neuroregenerative drugs against Alzheimer's disease.

Setbacks and promises for drugs against Alzheimer's disease

“…In regard to small molecules, two main approaches have been pursued: targetbased strategies to inhibit signaling pathways and proteins such as HDAC, kinases, and neutrophins, and cell-based phenotypic screens of small-molecule libraries [10]. The concept focuses on stimulating the regeneration of neural stem cells and the activation of neuroprotective pathways through small molecules and nanomedicines.…”

“…The concept focuses on stimulating the regeneration of neural stem cells and the activation of neuroprotective pathways through small molecules and nanomedicines. In regard to small molecules, two main approaches have been pursued: targetbased strategies to inhibit signaling pathways and proteins such as HDAC, kinases, and neutrophins, and cell-based phenotypic screens of small-molecule libraries [10].…”

A Focused Library of Psychotropic Analogues with Neuroprotective and Neuroregenerative Potential

“…5 These frustrating aspects fueled many researchers to question whether the viability of neurodegenerative targets for treating AD and related dementia might yield disease-modifying drugs. 6 Indeed, in addition to the classical "positive" neurodegeneration lesions, such as Aβ plaques and neurofibrillary tangles, characteristic losses of neurons and synaptic elements are core "negative" features. 7 Particularly, a significant reduction of neuronal density caused by cell death in specific hippocampal areas is one of the major hallmarks of AD progression.…”

“…7 This suggests the need for restorative intervention and prompts the pharmaceutical community to 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 explore the emerging possibility of targeting neuroprotection and neuroregeneration. 6,[8][9][10] In principle, activating endogenous neuroprotective pathways and sustaining brain neurogenesis could be more effective than blocking Aβ-and tau-mediated toxic cascades leading to neurodegeneration. 6,[8][9][10] On this basis, small molecules might prevent death and restore function to damaged neurons by directly targeting neuroprotective mechanisms.…”

Medicinal Chemistry Advances in Neurodegenerative Disease Therapy: Part 2

“…The first of the review articles in this issue, from our guest editor Bolognesi and co-workers investigates the interesting possibility of targeting neuroregeneration over neurodegeneration as a strategy for Alzheimer's disease drug discovery [6]. The authors highlight that targeting the endogenous brain regenerative process using small molecules or nanoparticles may be more beneficial for patient outcomes than therapies aimed at reverting neurodegeneration.…”