Targeting Metabolic Dysregulation in Alzheimer’s Disease: A Potential Therapeutic Strategy

Synaptosome microRNAs: emerging synapse players in aging and Alzheimer’s disease

Metabotropic glutamate receptor 1 alpha: a unique receptor variant with variable implications for Alzheimer's disease pathogenesis.

EVALUATING THE ASSOCIATION BETWEEN MITOCHONDRIAL DYSFUNCTION AND COGNITIVE DECLINE IN ALZHEIMER'S DISEASE

Memory loss in Alzheimer's disease: are the alterations in the UPR network involved in the cognitive impairment?

Rac1b Increases with Progressive Tau Pathology within Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease

Is the mitochondrial outermembrane protein VDAC1 therapeutic target for Alzheimer's disease?

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, behavioral impairments, and psychiatric comorbidities. The pathogenesis of AD remains incompletely elucidated, despite advances in dominant hypotheses such as the β-amyloid (Aβ) cascade, tauopathy, cholinergic deficiency, and neuroinflammation mechanisms. However, these hypotheses inadequately explain the multifactorial nature of AD, which exposes limitations in our understanding of its mechanisms. Mitochondrial dysfunction is known to play a pivotal role in AD, and since patients exhibit intracellular mitochondrial dysfunction and structural changes in the brain at an early stage, correcting the imbalance of mitochondrial homeostasis and the cytopathological changes caused by it may be a potential target for early treatment of AD. Mitochondrial structural abnormalities accelerate AD pathogenesis. For instance, structural and functional alterations in the mitochondria-associated endoplasmic reticulum membrane (MAM) can disrupt intracellular Ca2⁺ homeostasis and cholesterol metabolism, consequently promoting Aβ accumulation. In addition, the overaccumulation of Aβ and hyperphosphorylated tau proteins can further damage neurons by disrupting mitochondrial integrity and mitophagy, thereby amplifying pathological aggregation and exacerbating neurodegeneration in AD. Furthermore, Aβ deposition and abnormal tau proteins can disrupt mitochondrial dynamics through dysregulation of fission/fusion proteins, leading to excessive mitochondrial fragmentation and subsequent dysfunction. Additionally, hyperphosphorylated tau proteins can impair mitochondrial transport, resulting in axonal dysfunction in AD. This article reviews the biological significance of mitochondrial structural morphology, dynamics, and mitochondrial DNA (mtDNA) instability in AD pathology, emphasizing mitophagy abnormalities as a critical contributor to AD progression. Additionally, mitochondrial biogenesis and proteostasis are critical for maintaining mitochondrial function and integrity. Impairments in these processes have been implicated in the progression of AD, further highlighting the multifaceted role of mitochondrial dysfunction in neurodegeneration. It further discusses the therapeutic potential of mitochondria-targeted strategies for AD drug development.

Recent structural and functional studies of mitochondria have revealed that abnormalities in mitochondria may lead to mitochondrial dysfunction in aged individuals and those with neurodegenerative diseases, including Alzheimer's disease (AD). Molecular, cellular, and biochemical studies of animal models of aging and AD have provided compelling evidence that mitochondria are involved in AD development and progression. Further, a role for mitochondrial dysfunction in AD is supported by studies of neurons from autopsy specimens of patients with AD, transgenic AD mice, and neuronal cells expressing human AD mutation, which have revealed that amyloid beta (Abeta) enters mitochondria early in the disease process and disrupts the electron-transport chain, generates reactive oxygen species, and inhibits the production of cellular ATP, which in turn prevents neurons from functioning normally. Although AD researchers are actively involved in understanding Abeta toxicity and trying to develop strategies to reduce Abeta toxicity, one route they have yet to take is to investigate the molecules that activate nonamyloidogenic alpha-secretase activity that may reduce Abeta production and toxicity. In addition, it may be worthwhile to develop mitochondrially targeted antioxidants to treat AD. This article discusses critical issues of mitochondria causing dysfunction in aging and AD and discusses the strategies to protect neurons caused by mitochondrial dysfunction.

Alzheimer's disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Alzheimer's disease is an increasingly prevalent disease with 5.3 million people in the United States currently affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8 million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily affecting the aging population, characterized by progressive cognitive decline. Traditional models of AD pathogenesis, including the amyloid cascade and tau hypotheses, have not yielded definitive therapeutic breakthroughs. Emerging research suggests that metabolic dysfunction, particularly in glucose transport, plays a central role in AD progression. The glucose transporter 1 (GLUT1), which facilitates glucose entry across the blood-brain barrier, is crucial for maintaining brain energy metabolism. Studies have shown reduced GLUT1 expression in AD brains, impairing cerebral glucose uptake and contributing to neuronal dysfunction and neurodegeneration. This review synthesizes current evidence on the interplay between GLUT1 alteration and AD, highlighting how disruptions in glucose transport can exacerbate the disease's neuropathological features, including amyloid and tau pathologies. Furthermore, we explore potential therapeutic strategies aimed at restoring GLUT1 function, such as gene therapy, ketogenic diets, and small molecules that enhance GLUT1 expression. These approaches may offer promising avenues to mitigate the metabolic dysfunction driving AD and improve patient outcomes. This work underscores the importance of integrating metabolic insights into AD research to develop innovative therapeutic targets and interventions.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by cognitive decline. However, there is growing recognition of the significant impact of motor dysfunction in individuals affected by AD. These motor impairments contribute substantially to functional decline, reduced quality of life, and increased caregiver burden in AD patients.1 Current research efforts are increasingly focused on identifying motor dysfunction as a potential early marker in the progression of AD. The temporal relationship between motor and cognitive decline is under intense investigation, with studies suggesting that subtle motor changes, such as gait and balance disturbances or slowed walking speed, may precede detectable cognitive impairment by several years.2 Specifically, research indicates that gait speed predicts a decline in processing speed and visuospatial abilities, and in ApoE4 carriers, it also predicts a memory decline.3 One study found that increased amyloid-beta (Aβ) deposition is associated with reduced gait speed, muscle strength, and balance in cognitively impaired older adults.4 Emerging evidence strongly supports the inclusion of motor function assessments, particularly gait analysis, in the early detection and risk stratification of AD. This could enable earlier interventions and potentially lead to improved disease management. Technological advancements provide increasingly sophisticated non-invasive methods for detecting motor impairments in AD, potentially enabling earlier and more accurate diagnoses. Digital tools and applications-including smartphone-based assessments and virtual reality platforms-are being explored for objective and quantitative evaluation of mobility. These digital measures offer the potential for longitudinal data collection and the detection of subtle changes in motor function over time.5 Digital biomarkers provide the advantage of frequent, objective monitoring in real-world settings, potentially capturing early motor changes that may be missed by traditional clinical evaluations.6 Nonetheless, challenges remain regarding validation, standardization, and the influence of variables such as demographics and disease stage. Wearable devices offer the potential for continuous, non-invasive monitoring of motor behavior, revealing subtle changes indicative of early AD. However, interpreting data from these devices requires careful consideration and further validation in larger studies. Additionally, recent applications of MRI, PET, and other neuroimaging techniques are being examined to detect brain changes related to motor dysfunction in AD. Advanced MRI techniques, such as diffusion tensor imaging (DTI), are used to assess white matter integrity along motor pathways, while molecular PET imaging can visualize amyloid and tau pathology in brain regions associated with motor control.7 Of note, tau pathology in higher motor regions has been significantly associated with cognitive decline. Advanced neuroimaging is essential for visualizing structural and functional brain changes linked to AD, including those that impact motor control.8 These methods may assist in early diagnosis, differential diagnosis from other dementias, and monitoring disease progression. Current therapeutic approaches to managing motor dysfunction in AD include both pharmacological and non-pharmacological interventions. Clinical trials specifically targeting motor symptoms in AD with pharmacological treatments are limited. Management typically relies on drugs primarily aimed at cognitive symptoms, which may have secondary benefits on motor function. Cholinesterase inhibitors (donepezil, rivastigmine) and memantine, which are approved for cognitive symptoms, have shown mild effects on motor function (e.g., donepezil restores mitochondrial respiratory function in skeletal muscles).9 Emerging disease-modifying therapies targeting amyloid and tau, and their potential indirect effects on motor function, are under investigation. Non-pharmacological interventions, particularly physical therapy tailored to improve balance, gait, and muscle strength, play a key role in managing motor symptoms and enhancing functional independence and safety. Physical activity can improve brain function and memory and may delay functional decline. Combined training that integrates motor and cognitive exercises (dual-task training) may provide additional benefits. Music therapy has also been shown to positively influence cognitive status, emotional well-being, and quality of life in older adults with early-stage dementia.10 Motor impairments are increasingly recognized as early markers of disease progression and critical targets in the comprehensive care of AD. Improving mobility, balance, and functional independence may result in greater patients' autonomy and reduced physical and emotional strain on caregivers.

Impaired glucose metabolism, especially glycolytic arrest, is strongly associated with Alzheimer's disease (AD), but its systemic changes in the AD brain are not well defined. Here, we performed an integrated analysis of AD brain transcriptomics, combined with cognitive scoring, tau pathology grading data, to reveal systemic alterations of 28 glycolysis-related genes. Most genes, including glucose-6-phosphate isomerase (GPI), phosphofructokinase, muscle type (PFKM) and lactate dehydrogenase A (LDHA), were downregulated and correlated with cognitive decline (Mini-Mental State Examination, Clinical Dementia Rating) and tau pathology severity (correlation analysis, p < 0.05). These genes exhibited robust diagnostic potential (receiver operating characteristic area under the curve = 0.679-0.803), highlighting their utility as early AD biomarkers. Notably, OVO-like zinc finger 2 (OVOL2), a transcriptional repressor of glycolysis, was upregulated in AD and positively associated with tau burden and the suppression of GPI, PFKM and LDHA. Functional studies demonstrated that OVOL2 knockdown restored glycolytic gene expression and attenuated tau pathology, suggesting that OVOL2 is a candidate upstream regulatory factor for AD metabolic disorders. Taken together, glycolysis enzymes were systemically altered in AD progression, and OVOL2 may be a candidate upstream regulator, while GPI, PFKM and LDHA may be potential diagnostic and therapeutic targets.

Alzheimer's disease (AD) is thought to start years or decades prior to clinical diagnosis. Overt pathology such as protein misfolding and plaque formation occur at later stages, and factors other than amyloid misfolding contribute to the initiation of the disease. Vascular and metabolic dysfunctions are excellent candidates, as they are well-known features of AD that precede pathology or clinical dementia. While the general notion that vascular and metabolic dysfunctions contribute to the etiology of AD is becoming accepted, recent research suggests novel mechanisms by which these/such processes could possibly contribute to AD pathogenesis. Vascular dysfunction includes reduced cerebrovascular flow and cerebral amyloid angiopathy. Indeed, there appears to be an interaction between amyloid β (Aβ) and vascular pathology, where Aβ production and vascular pathology both contribute to and are affected by oxidative stress. One major player in the vascular pathology is NAD(P)H oxidase, which generates vasoactive superoxide. Metabolic dysfunction has only recently regained popularity in relation to its potential role in AD. The role of metabolic dysfunction in AD is supported by the increased epidemiological risk of AD associated with several metabolic diseases such as diabetes, dyslipidemia and hypertension, in which there is elevated oxidative damage and insulin resistance. Metabolic dysfunction is further implicated in AD as pharmacological inhibition of metabolism exacerbates pathology, and several metabolic enzymes of the glycolytic, tricarboxylic acid cycle (TCA) and oxidative phosphorylation pathways are damaged in AD. Recent studies have highlighted the role of insulin resistance, in contributing to AD. Thus, vascular and metabolic dysfunctions are key components in the AD pathology throughout the course of disease. The common denominator between vascular and metabolic dysfunction emerging from this review appears to be oxidative stress and Aβ. This review also provides a framework for evaluation of current and future therapeutics for AD.

Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by the presence of extracellular amyloid-β (Aβ) aggregates and intracellular neurofibrillary tangles formed by hyperphosphorylated tau as pathological features and the cognitive decline as main clinical features. An important cellular correlation of cognitive decline in AD is synapse loss. Soluble Aβ oligomer has been proposed to be a crucial early event leading to synapse dysfunction in AD. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function have been suggested in the pathogenesis of AD. Astrocytes may contribute to synapse dysfunction at an early stage of AD by participating in Aβ metabolism, brain inflammatory response, and synaptic regulation. While mesenchymal stem cells can inhibit astrogliosis, and promote non-reactive astrocytes. They can also induce direct regeneration of neurons and synapses. This review describes the role of mesenchymal stem cells and underlying mechanisms in regulating astrocytes-related Aβ metabolism, neuroinflammation, and synapse dysfunction in early AD, exploring the open questions in this field.

Although the role of gut microbiota (GMB)-derived metabolites in mitochondrial and endolysosomal dysfunction in Alzheimer’s disease (AD) under metabolic syndrome remains unclear, deciphering these host–metabolite interactions represents a major public health challenge. Dysfunction of mitochondria and endolysosomal networks (ELNs) plays a crucial role in metabolic syndrome and can exacerbate AD progression, highlighting the need to study their reciprocal regulation for a better understanding of how AD is linked to metabolic syndrome. Concurrently, metabolic disorders are associated with alterations in the composition of the GMB. Recent evidence suggests that changes in the composition of the GMB and its metabolites may be involved in AD pathology. This review highlights the mechanisms of metabolic syndrome-mediated AD development, focusing on the interconnected roles of mitochondrial dysfunction, ELN abnormalities, and changes in the GMB and its metabolites. We also discuss the pathophysiological role of GMB-derived metabolites, including amino acids, fatty acids, other metabolites, and extracellular vesicles, in mediating their effects on mitochondrial and ELN dysfunction. Finally, this review proposes therapeutic strategies for AD by directly modulating mitochondrial and ELN functions through targeting GMB metabolites under metabolic syndrome.