Humberto Martínez-Orozco

Blood-brain barrier (BBB) dysfunction is increasingly recognized as an early pathological event in sporadic Alzheimer’s disease (AD), which represents over 95% of cases. Vascular risk factors and cerebral insulin resistance are considered potential contributors to its initiation. This review synthesizes evidence available through March 2026 on the temporal progression of morphological, functional, and molecular BBB alterations in AD patients and experimental models. This review emphasizes the proposed role of BBB disruption in perpetuating neurodegeneration through feedback loops involving pericyte damage, hypoxia, perivascular inflammation, and dysregulation of amyloid-β transport systems. By integrating data from neuroimaging, fluid biomarkers, and post-mortem studies, available evidence suggests that BBB alterations can be detected from preclinical stages, most consistently in the hippocampus, and may exhibit sex-specific differences. The review compares findings from familial transgenic models with the more limited characterization available in sporadic AD models (notably the intracerebroventricular streptozotocin model), and highlights key knowledge gaps regarding temporal dynamics. This synthesis supports further exploration of strategies to preserve BBB integrity. An integrated vascular approach may usefully complement current amyloid- and tau-centered therapies, particularly in sporadic AD.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by intersecting pathological processes. Persistent attrition in AD drug‐development pipelines highlights the limited clinical impact of single‐target therapies and has increased interest in multi‐target approaches acting on shared biological hubs. Although recent strategies extend beyond amyloid‐centered interventions, much of the evidence supporting multifunctional compounds remains preclinical or shows heterogeneous outcomes in advanced clinical stages. This narrative review examines drug candidates that have entered Phase III clinical trials in the last decade, with emphasis on emerging multitarget pharmacotherapies such as muscarinic M1 receptor agonists, dual M1/sigma‐1 receptor (σ1R) agonists, and dual σ1R agonist/anti‐amyloid agents. We also discuss complementary non‐pharmacological interventions, including physical exercise and targeted nutrition, that may support cognitive and emotional outcomes. Finally, we propose the Synergistic Optimized Pharmacological and Holistic Interventions for AD (SOPHI‐AD) framework as a conceptual and testable approach integrating multitarget pharmacology with lifestyle‐based strategies for AD management.

Memory processes are susceptible to impairment induced by excessive consumption of hypercaloric diets, particularly those rich in saturated fats and fructose. Such dietary patterns have been linked to disrupted neurotransmission in the prefrontal cortex (PFC), where the balance between excitation and inhibition depends on efficient glucose metabolism and the synthesis of neuroactive amino acids. However, the molecular mechanisms underlying these effects remain poorly understood. Here, male C57BL/6 mice were fed for 10 weeks with a control diet, a high-fat diet (HFD), a high-fructose diet (HFrD), or a combined high-fat/high-fructose diet (HFFrD). Their body weight gain and visceral adiposity were primarily driven by saturated fat intake, whereas hyperglycemia was observed across all diets. Also, we assessed metabolic outcomes, recognition memory, and PFC molecular profiles, including neuroactive amino acids (GABA, glutamate, glutamine, aspartate, alanine, glycine, and taurine) and the expression of genes related to glucose metabolism ( Slc2a1 , Pcx , G6pd , Gck , Pck1 , Irs2 ) and the glutamate/GABA–glutamine cycle ( Glul , Glud1 , Gad1 , Gad2 ). Behaviorally, HFFrD reduced locomotor activity and caused the most significant impairment in recognition memory. In the PFC, diet composition generated distinct amino acid profiles, revealing vulnerability of the glutamine–glutamate–GABA cycle to hypercaloric intake. Transcriptional responses were diet-specific, with consistent Gad1 upregulation and broader induction of glucose metabolism–related genes. Together, these findings demonstrate diet-dependent metabolic and neurochemical remodeling in the PFC and support a link between excessive fat and/or fructose intake with disrupted glutamine–glutamate homeostasis and memory deficits.

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) and chronic neuroinflammation, with microglia playing a central role in its pathogenesis. Alterations in microglial metabolism have been proposed to contribute to AD-related inflammatory responses and reduced Aβ clearance, suggesting that thiamine-dependent pathways may be relevant in this context. Thiamine pyrophosphate (TPP), the active form of vitamin B1, is essential for glucose metabolism and mitochondrial function; however, its association with microglial changes in AD remains unclear. In this study, 9-month-old female triple-transgenic AD (3xTg-AD) mice and non-transgenic controls (NoTg) received TPP (2.0 mg/mL) or saline as a vehicle for six weeks via osmotic pumps. Nesting, a hippocampus-dependent behavioral test, as well analyses of Aβ burden, microglial morphology, and the expression of genes related to metabolic and immune pathways were evaluated. Differences in nesting behavior between experimental groups were observed, but TPP treatment was not associated with an evident change in 3xTg-AD mice. In the subiculum and CA1 regions of the hippocampus of female 3xTg-AD mice exposed to TPP, a lower Aβ burden was observed, and morphological variations in microglia were detected in both groups (3xTg-AD and NoTg). Additionally, in the brain of the TPP-treated group, some changes in mRNA gene expression were recorded. Together, these findings describe hippocampal microglial and amyloid profiles following TPP treatment in 3xTg-AD mice and provide a basis for further investigation of thiamine-dependent pathways in AD-related neuroinflammatory contexts.

The complexity of Alzheimer’s disease (AD) pathophysiology represents a significant challenge in the development of effective therapeutic agents for its treatment. CNEURO-201 (CN, also Amylovis-201) is a novel pharmaceutical agent with dual activity as an anti-amyloid-β (Aβ) agent and σ1 receptor agonist. CN exhibits great efficacy at very low doses, delaying cognitive impairment and alleviating Aβ load in animal models of AD. However, CN functions on other remains related to this pathology remain to be investigated. The present study sought to evaluate the effects of CN treatment at a dosage of 0.1 mg kg⁻¹ (p.o) over an eight-week period in the 3xTg-AD mouse model. In silico studies, as well as biochemical and immunofluorescence assays, were conducted on brain tissue to investigate the CN effects on acetylcholine metabolism, redox system, and glial cell activation-related biomarkers in brain regions that are relevant for memory. The results demonstrated that CN effectively rescues cognitive impairment of 3xTg-AD mice by influencing glial activity to reduce existing Aβ plaques but also modulating acetylcholine metabolism and the enzymatic response of proteins involved in the redox system. Our outcomes reinforced the potential of CN in treating AD by acting on multiple pathways altered in this disease.

The complexity of Alzheimer’s disease (AD) pathophysiology represents a significant challenge in the development of effective therapeutic agents for its treatment. CNEURO-201 (CN, also Amylovis-201) is a novel pharmaceutical agent with dual activity as an anti-amyloid-β (Aβ) agent and σ1 receptor agonist. CN exhibits a great efficacy at very low doses, delaying cognitive impairment and alleviating Aβ load in animal models of AD. However, CN functions on other pathways related to this pathology remains to be investigated. The present study sought to evaluate the effects of CN treatment at a dosage of 0.1 mg kg-1 (p.o) over an eight-week period in the 3xTg-AD mouse model. In silico studies, as well as biochemical and immunofluorescence assays, were conducted on brain tissue to investigate the CN effects on acetylcholine metabolism, redox system and glial cell activation related biomarkers in brain regions that are relevant for memory. The results demonstrated that CN effectively rescues cognitive impairment of 3xTg-AD mice by influencing glial activity to reduce existing Aβ plaques, but also modulating acetylcholine metabolism and the enzymatic response of proteins involved in redox system. Our outcomes reinforced the potential of CN to treat AD by acting on multiple pathways altered in this disease.

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide, profoundly impacts health and quality of life. While cognitive impairments—such as memory loss, attention deficits, and disorientation—predominate in AD, motor symptoms, though common, remain underexplored. These motor symptoms, including gait disturbances, reduced cardiorespiratory fitness, muscle weakness, sarcopenia, and impaired balance, are often associated with advanced stages of AD and contribute to increased mortality. Emerging evidence, however, suggests that motor symptoms may be present in earlier stages and can serve as predictive markers for AD in older adults. Despite a limited understanding of the underlying mechanisms driving these motor symptoms, several key pathways have been identified, offering avenues for further investigation. This review provides an in-depth analysis of motor symptoms in AD, discussing its progression, potential mechanisms, and therapeutic strategies. Addressing motor symptoms alongside cognitive decline may enhance patient functionality, improve quality of life, and support more comprehensive disease management strategies.

Human α-synuclein is a small monomeric protein (140 residues) essential to maintain the function of the dopaminergic neurons and the neuronal redox balance. However, it holds a dark side since it is able to clump inside the neurons forming insoluble aggregates known as Lewy bodies, which are considered the hallmark of Parkinson’s disease. Sporadic mutations and non-enzymatic post-translational modifications are well-known to stimulate the formation of Lewy bodies. Yet, the effect of non-enzymatic post-translational modifications on the function of α-synuclein has been studied less intense. Therefore, here we study how nitration and glycation mediated by methylglyoxal affect the redox features of α-synuclein. Both diminish the ability of α-synuclein to chelate Cu²⁺, except when N^ε-(carboxyethyl)lysine or N^ε-(carboxymethyl)lysine (two advanced glycation end products highly prevalent in vivo) are formed. This results into a lower capacity to prevent the Cu-catalyzed ascorbic acid degradation and to delay the formation of H₂O₂. However, only methylglyoxal was able to abolish the ability of α-synuclein to inhibit the free radical release. Both nitration and glycation enhanced the α-synuclein availability to be damaged by O₂^·-, although glycation made α-synuclein less reactive towards HO·. Our data represent the first report describing how non-enzymatic post-translational modifications might affect the redox function of α-synuclein, thus contributing to a better understanding of its pathological implications.