Therapeutic Convergence in Neurodegeneration: Natural Products, Drug Repurposing, and Biomolecular Targets

Neurodegenerative diseases pose an escalating global health burden, caused by their intricate pathophysiological mechanisms, and consequently, a persistent lack of curative therapies. A detailed exploration of these concepts, and of those presented below in this work, can be found in the Special Issue “Biomolecular Approaches and Drugs for Neurodegeneration”, available at https://www.mdpi.com/journal/biomolecules/special_issues/O40SG4E9N5 (accessed on 30 August 2025). Importantly, recent advances in molecular neuroscience have elucidated key processes underlying disorders such as Alzheimer’s disease, Parkinson’s disease, prion disorders, multiple sclerosis, and spinocerebellar ataxia type 1 [1,2,3]. These conditions share common features including selective neuronal vulnerability, dysregulated lipid metabolism, mitochondrial dysfunction, neuroinflammation, and protein misfolding. Emerging prophylactic [4] and therapeutic strategies increasingly target these converging pathways, with the latter leveraging both natural compounds and synthetic agents to restore cellular homeostasis and mitigate neurodegeneration [5,6,7,8,9]. Notably, neuropeptides play a multifaceted role in the pathophysiology of Alzheimer’s disease [10]. Alterations in their expression and receptor activity have been observed in affected brain regions, particularly the hippocampus and entorhinal cortex. These molecules contribute to neuroprotection by modulating synaptic plasticity, reducing beta-amyloid accumulation, enhancing glucose metabolism, and regulating stress responses such as endoplasmic reticulum stress and autophagy. Their involvement in key signaling pathways suggests that neuropeptides may serve not only as biomarkers of disease progression, but also as promising therapeutic targets for intervention in Alzheimer’s disease [10,11]. Complementing these molecular insights, recent findings have highlighted the role of microglial responses to myelin debris in aging brains, which contribute to cholesterol ester accumulation, a process implicated in neurodegenerative progression. This accumulation can be attenuated by ACAT1 inhibition, which promotes ABCA1-mediated cholesterol efflux via the LXR pathway [12,13]. Interestingly, these findings underscore the therapeutic relevance of lipid regulation in neurodegenerative contexts. Technological innovations such as protein misfolding cyclic amplification (PMCA) [14] have enabled cross-species screening of anti-prion compounds, identifying methylene blue as a potent inhibitor of prion replication [14,15] and validating PMCA’s utility in drug selectivity and structure–activity profiling. Moreover, in Parkinson’s disease models, high-throughput screening of marine and plant-derived fractions has uncovered bioactive molecules capable of alleviating mitochondrial stress, highlighting the untapped potential of natural products [16,17,18]. Among these, dehydrozingerone and its dimeric form have demonstrated notable neuroprotective effects in animal models, preserving dopaminergic neurons and motor function [19]. Similarly, ladostigil (N-propargyl-(3R)-aminoindan-5-yl)-N-propylcarbamate) [20,21] has shown promise in aging rats by modulating immune regulators such as TNFAIP3 and EGR1, thereby reducing memory decline and neuroinflammation [22]. Within the expanding realm of plant-derived therapeutics, Syzygium aromaticum (clove) [23,24] has emerged as a compelling candidate for intervention in Alzheimer’s disease, with its phytochemicals and amino acids contributing to antioxidant defense, anti-inflammatory activity, and neurotransmitter modulation [25,26]. Across various neurodegenerative conditions, research into adrenergic receptors suggests that repurposing existing drugs may offer new therapeutic avenues for Alzheimer’s disease [27], despite their incomplete mechanistic clarity. Other drug repurposing studies have highlighted the potential of atomoxetine [28] as part of neuroprotective strategies, including in the context of Alzheimer’s disease. Notably, a phase II clinical trial demonstrated excellent safety, tolerability, and target engagement in individuals with mild cognitive impairment, all advantages of repurposing a well-characterized FDA-approved medication [29]. Remarkably, in multiple sclerosis, immunoglobulin G and complement activation have been implicated in demyelination and neuronal damage, reinforcing the role of immune dysregulation in disease progression [30,31]. In parallel, spinocerebellar ataxia type 1 has inspired diverse therapeutic approaches, including genetic, pharmacological, and cellular investigations, aimed at preserving Purkinje cells and restoring motor coordination [32,33]. Meanwhile, nuclear medicine continues to refine TSPO radiotracers [34] for dementia imaging [35,36,37], with newer compounds addressing limitations in sensitivity and specificity (

Table 1. Overview of the pathological features, therapeutic strategies, and technological innovations herein discussed for some of the main neurodegenerative diseases.

Disease/Condition	Key Pathological Features	Therapeutic Strategies/Compounds
Alzheimer’s disease	Neuronal vulnerability, metabolic stress, proteotoxicity, protein misfolding	Syzygium aromaticum (clove), adrenergic receptor-targeting drugs, antioxidant and neurotransmitter support
Parkinson’s disease	Mitochondrial dysfunction, dopaminergic neuron loss	Dehydrozingerone and its dimer (in Drosophila), marine/plant-derived bioactives
Prion disorders	Protein misfolding, cross-species infectivity	Methylene blue
Multiple sclerosis	Myelin debris, cholesterol ester accumulation, immune dysregulation	ACAT1 inhibition, ABCA1-mediated cholesterol efflux via LXR pathway
Spinocerebellar ataxia type 1	Purkinje cell degeneration, motor coordination loss	Genetic, pharmacological, and cellular therapies
Aging brain	Lipid metabolism dysregulation, neuroinflammation, mitochondrial stress, protein misfolding	Natural compounds, synthetic agents, drug repurposing
Alzheimer’s disease	Cholesterol accumulation, immune activation	Ladostigil (modulates TNFAIP3 and EGR1), ACAT1 inhibition
	Neuronal vulnerability, metabolic stress, proteotoxicity, protein misfolding	Syzygium aromaticum, adrenergic receptor-targeting drugs, antioxidant and neurotransmitter support

For further details, readers are invited to consult the Special Issue “Biomolecular Approaches and Drugs for Neurodegeneration”, available at https://www.mdpi.com/journal/biomolecules/special_issues/O40SG4E9N5 (accessed on 30 August 2025).

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Altogether, these multidisciplinary efforts reflect a rapidly evolving landscape in neurodegenerative disease research. By integrating molecular insights, pharmacological innovation, and diagnostic precision, the field is advancing toward targeted interventions that address both etiological mechanisms and clinical manifestations. The convergence of natural product discovery, drug repurposing, and imaging technologies offers renewed promise for reducing disease burden and improving patient outcomes.