Molecular Mechanisms and Drug Research in Alzheimer’s Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 1 September 2026 | Viewed by 2261

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Guest Editor
Neurochemistry Lab, Department of Psychiatry, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Charlestown, MA 02129, USA
Interests: aging; exposome and exposomics; Alzheimer’s disease; Parkinson’s disease; depression; artificial intelligence; machine and deep learning; big data analytics; blockchain; stigma; socially assistive robotics; virtual/augmented/mixed reality; cancer
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Special Issue Information

Dear Colleagues,

Alzheimer's disease (AD) remains a devastating senile dementia, characterized by progressive cognitive decline and neuronal demise. Despite extensive research, its complex and multifactorial pathogenesis—involving Ab amyloid plaques, neurofibrillary tangles (NFTs), neuroinflammation, synaptic dysfunction, genetic factors, etc.—is not fully understood. This incomplete mechanistic picture significantly hinders the development of truly effective disease-modifying therapies, as evidenced by the limited success of current treatments and many clinical trial setbacks. This Special Issue focuses on advancing our understanding of the molecular mechanisms underpinning AD etiopathogenesis and translating this knowledge into innovative therapeutic strategies. We invite original research articles, reviews, and perspectives that delve into novel signaling pathways, protein misfolding and aggregation, genetic and epigenetic regulators, mitochondrial dysfunction, glial cell contributions, synaptic integrity, dysbiosis, oxidative stress, neuroinflammation, metal homeostasis, the roles of the lood–brain barrier (BBB) and gut-brain axis, and so on. A core emphasis will be placed on translational research highlighting novel drug targets; the development and preclinical and clinical evaluation of small molecules, biologics, or repurposed drugs; biomarkers for therapeutic response; and innovative drug delivery approaches. The goal is to integrate novel findings and cutting-edge technologies, such as AI-based techniques, and accelerate the pipeline from mechanistic discovery to promising AD therapeutic candidates.

Dr. Xudong Huang
Guest Editor

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Keywords

  • Alzheimer's disease
  • molecular mechanisms
  • drug discovery
  • Aβ amyloid
  • tau protein
  • neuroinflammation
  • oxidative stress
  • metal homeostasis
  • blood–brain barrier
  • dysbiosis

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Published Papers (2 papers)

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Research

18 pages, 25952 KB  
Article
Intranasal Adipose-Derived MSC Extracellular Vesicles Confer Sustained Cognitive Improvement and Suppress Alzheimer’s Pathology in APP/PS1 Mice
by Mengsi Tian, Renjun Feng, Chunmei Gong, Xinyu Ben, Zhijian Ma, Xinan Yi and Qingyun Guo
Biomolecules 2026, 16(6), 798; https://doi.org/10.3390/biom16060798 - 28 May 2026
Viewed by 474
Abstract
Alzheimer’s disease (AD) lacks effective disease-modifying therapies, and extracellular vesicles (EVs) derived from adipose-derived mesenchymal stromal cells (ADMSCs) have emerged as promising therapeutic candidates. In this study, we investigated the brain biodistribution and dose-dependent effects of intranasally administered ADMSC-EVs in female APP/PS1 mice, [...] Read more.
Alzheimer’s disease (AD) lacks effective disease-modifying therapies, and extracellular vesicles (EVs) derived from adipose-derived mesenchymal stromal cells (ADMSCs) have emerged as promising therapeutic candidates. In this study, we investigated the brain biodistribution and dose-dependent effects of intranasally administered ADMSC-EVs in female APP/PS1 mice, with age-matched wild-type mice and vehicle-treated transgenic mice serving as controls. EV biodistribution was assessed using PKH26 labeling, cognitive performance was evaluated using the Morris water maze, Y-maze, and novel object recognition tests, and hippocampal amyloid pathology and plasma AD-related biomarkers were analyzed. Intranasally delivered ADMSC-EVs rapidly reached multiple brain regions, including the hippocampus, improved learning and memory performance, and reduced hippocampal amyloid-β 1-42 (Aβ42) deposition and plaque burden. These effects followed a nonlinear dose–response pattern, with reduced efficacy at low doses and no additional benefits at high doses. Notably, partial behavioral and pathological benefits persisted after treatment cessation. Together, these findings show that intranasal ADMSC-EVs exert therapeutic effects in APP/PS1 mice and support the importance of dose optimization and post-treatment durability in the development of EV-based interventions for AD. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Drug Research in Alzheimer’s Disease)
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24 pages, 2282 KB  
Article
ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer’s Disease
by Silvia Lope-Piedrafita, Gabriel Serra-Mir, Paula Melón, Anna Bonaterra, Mar Hernández-Guillamon and Sandra Villegas
Biomolecules 2025, 15(11), 1602; https://doi.org/10.3390/biom15111602 - 15 Nov 2025
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Abstract
The occurrence of amyloid-related imaging abnormalities (ARIAs), found in clinical trials for Aβ-immunotherapy, has been related to the antibody’s effector function on glial activation by the Fc portion of the antibody. The use of single-chain variable fragments (scFv) has been proposed as a [...] Read more.
The occurrence of amyloid-related imaging abnormalities (ARIAs), found in clinical trials for Aβ-immunotherapy, has been related to the antibody’s effector function on glial activation by the Fc portion of the antibody. The use of single-chain variable fragments (scFv) has been proposed as a safer therapeutic strategy. Here, the effects of the mice format of bapineuzumap (mAb-m3D6) and its scFv (scFv-h3D6) on the occurrence of ARIAs in the APP23 mouse model of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) have been addressed by magnetic resonance imaging (MRI). Results are supported by histological and/or biochemical determinations. Aged APP23 mice showed a significantly higher number of microhemorrhages than non-transgenic mice. mAb-m3D6 produced an increase in the number of new hemorrhagic events, mainly in the cortex, whereas scFv-h3D6 did not. Both mAb-m3D6 and scFv-h3D6 reduced Aβ levels by the same extent. Axonal/myelin damage was found in the frontal corpus callosum of APP23 mice, which did not recover after treatment. In conclusion, the scFv-h3D6 format appears safer than the full-length mAb in the APP23 model of AD and CAA. This finding is highly relevant in light of the new FDA- and EMA-approved mAbs, which exclude APOEε4 allele carriers due to the occurrence of hemorrhages. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Drug Research in Alzheimer’s Disease)
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