Aug 2026· Brain and Behavior· Vol 16· 1 citation· 160 references
Medicine
TL;DR
This review sought to integrate disease‐specific causative triggers with shared pathogenic pathways, focusing on neuroinflammatory signaling, oxidative imbalance, mitochondrial impairment, and disrupted protein homeostasis, in order to support multi‐target, disease‐modifying therapeutic strategies.
Abstract
Although Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD) present with markedly different clinical phenotypes, these neurodegenerative diseases (NDDs) appear to converge on a shared set of underlying molecular disturbances. This review sought to integrate disease‐specific causative triggers with shared pathogenic pathways, focusing on neuroinflammatory signaling, oxidative imbalance, mitochondrial impairment, and disrupted protein homeostasis, in order to support multi‐target, disease‐modifying therapeutic strategies.
Co-expression of tau and amyloid-beta with α-syn pathology is shown in over 50% of Parkinson’s Disease postmortem brains, and these patients present with enhanced cognitive decline and disease phenotype. This review integrates the known immune response in PD with co-pathology incidence, highlighting synergistic interactions between α-syn, tau and Aβ and how this promotes a distinct neuroinflammatory response leading to severe neuronal loss and cognitive symptoms. Based on this, we support the need for combinatorial therapeutic strategies to address this debilitating, yet common factor of disease.
Jhodi M. Webster, Ashley S. Harms· npj Parkinson's Disease· 0 citations
Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.
Neurodegenerative diseases are a heterogeneous group of chronic and progressive disorders, which are characterized by selective neuronal destruction, synaptic malfunction and progressive cognitive and locomotor dysfunction. The major ones are Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis which are a formidable and growing global health and socio-economic burden mainly due to demographic aging. Even despite the advances in the symptomatic treatment, predominantly through the cholinergic, dopaminergic, glutamatergic, and GABAergic system, the current treatment regimens are not able to stop the underlying neurodegenerative events or reverse them. There is mounting evidence that convergent pathogenic mechanisms, such as protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, impaired autophagy-lysosomal pathways, synaptic dysfunction, and chronic neuroinflammation, are convergent mechanisms. These convergent molecular and cellular cascades provide a strong rationale behind the identification of new neuropharmacological targets, which include: kinases, phosphatases, epigenetic regulators, neurotrophic signalling pathways and neuroimmune mediators. Advances in the biomarker discovery, genomics and systems biology have further enabled the use of precision based therapeutic stratification and early-intervention approaches. Genetic, nanotechnology, and RNA-based therapeutics as well as biologics are reconfiguring translational models in neurodegeneration. A mechanism-based, multi-target, precision neuropharmacological approach, as a group, has significant potential in achieving long-term neuroprotection, improved clinical and disease modification in neurodegenerative diseases.
Nisha, Sumairah Qadir· Current Pharmaceutical Resea...· 0 citations
Amyotrophic lateral sclerosis (ALS) and canine degenerative myelopathy (DM) are highly complex neurodegenerative diseases characterized by progressive motor impairment and associated with mutations in the SOD1 gene, sharing common genetic mechanisms. This review analyzed, from a translational perspective, recent therapeutic advances in DM with potential application to ALS. The findings demonstrate that the aggregation of mutant SOD1 protein plays a central role in neuronal degeneration and is influenced by factors such as microRNAs, protein structural instability, and cell-to-cell propagation. Promising therapeutic strategies include gene modulation, enhancement of macrophage migration inhibitory factor (MIF) activity, the use of mesenchymal stem cells, and curcumin, all of which have shown potential to slow disease progression and improve quality of life. DM stands out as an important natural model for the development of new therapies for ALS.
A lysosome-centered framework for understanding PGRN-related neurodegenerative pathologies is presented, and TMEM106B is discussed as a critical genetic modifier within this lysosomal network, highlighting its role in shaping disease risk and phenotypic heterogeneity.
The urgent need for reliable biomarkers, early diagnosis, and multidisciplinary disease-modifying strategies for future therapeutic interventions is highlighted, with particular emphasis on challenges associated with bench-to-bedside translation.
Jeewanjot Singh, Subhi Sharma, Prabhjot Singh et al.· Advances in Modern Biomedici...· 0 citations
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