As life expectancy increases worldwide, the proportion of people aged 65 and older is expected to double by 2050 and these global demographic shifts will be accompanied by an increase in age-related neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease (PD). AD is the leading cause of dementia worldwide, characterized by progressive cognitive decline linked to amyloid beta accumulation, tau pathology, neuronal cell death and chronic neuroinflammation. PD is the most common movement disorder worldwide, characterized by progressive motor decline linked to alpha-synuclein accumulation, formation of Lewy bodies and neurites, dopaminergic neuron death, as well as chronic neuroinflammation. Increasing evidence implicates inflammasomes, intracellular multiprotein complexes that orchestrate innate immune responses, as key drivers of the neuroinflammatory milieu in AD and PD. The NLRP3 inflammasome, mostly expressed by microglia, has been shown to activate caspase-1, resulting in the cleavage and release of pro-inflammatory cytokines IL-1β and IL-18 and promoting pyroptotic cell death within the central nervous system. This review synthesizes current knowledge on the molecular mechanisms of inflammasome activation, their pathological involvement in AD and PD, and the genetic underpinnings supporting their role. It further highlights emerging therapeutic strategies aimed at modulating inflammasome activity, evaluating preclinical outcomes and clinical trial progress. Understanding inflammasome dynamics provides critical insight into AD and PD pathophysiology and presents promising targets for future disease-modifying treatments.
Gene signatures of Alzheimer’s disease (AD) brains reflect the output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulations. To nominate candidate factors modulating these signatures, we developed a machine learning model to integrate cellular and molecular features explaining differential gene expression in AD. Among the features tested, YTHDF proteins, the canonical readers of N6-methyladenosine (m6A) RNA modification, are among the most influential predictors of AD gene signatures. Protein modules containing YTHDFs were downregulated in human AD brains, and knockdown or pharmacological inhibition of YTHDFs in iPSC-derived 2D and 3D neuronal models recapitulated key AD-associated gene signatures. Furthermore, eCLIP-seq revealed altered YTHDF binding to transcripts in AD brains, at both m6A-dependent and m6A-independent sites. Together, these results support an important role for YTHDF proteins in modulating AD-associated gene signatures in the human brain.
Age-associated remodeling of membrane lipid composition has been implicated in cellular dysfunction, yet the mechanisms linking lipid changes to membrane integrity and disease remain poorly defined. In the retinal pigment epithelium (RPE), lipid dysregulation is strongly associated with aging and age-related macular degeneration (AMD), a neurodegenerative disease of the central nervous system, but the causal pathways remain unclear. Here, we identify reduced activity of the lipid elongase ELOVL2 as a central driver of age-dependent membrane remodeling. Loss of ELOVL2-dependent polyunsaturated fatty acid (PUFA) elongation shifts plasma membrane lipid composition, leading to altered membrane biophysical properties and compromised membrane integrity. In response to this stress, RPE cells do not undergo apoptosis but instead activate a lysosome-dependent plasma membrane repair program that preserves barrier function under metabolic challenge. However, this adaptive response drives spatially polarized lysosomal exocytosis, promoting extracellular remodeling and accumulation of sub-RPE deposits associated with aging and AMD. Restoration of ELOVL2-derived lipid products reverses membrane abnormalities and suppresses lysosome-mediated remodeling phenotypes, demonstrating direct metabolic control of membrane homeostasis. Together, these findings define an ELOVL2-dependent lipid–lysosome axis that links PUFA elongation to plasma membrane integrity and reveals how compensatory repair mechanisms can contribute to tissue remodeling and disease progression in aging epithelia.
Alzheimer’s disease research is entering a period of rapid acceleration. After decades focused on identifying individual disease-associated proteins and pathways, the field is moving toward a deeper understanding of how these mechanisms interact to influence cellular function, biological systems, and ultimately behavior and cognition. The emphasis is moving from isolated molecular targets to coordinated biological systems. Underlying pathological mechanisms point toward the breakdown of core cellular maintenance systems, including proteostasis, metabolism, and immune regulation. This dysfunction propagates from organelles to cells, from cells to neural circuits, and, ultimately, to cognition and behavior. Moving beyond single-target approaches will depend on understanding these upstream drivers, how they interact, and how sex, genetic background, and accumulated stressors shape when and how these systems fail. Underlying pathological mechanisms point toward the breakdown of core cellular maintenance systems, including proteostasis, metabolism, and immune regulation. This dysfunction propagates from organelles to cells, from cells to neural circuits, and ultimately to cognition and behavior. The BrightFocus Alzheimer’s Disease Research (ADR) program [1] has long operated within this broad framework. Rather than focusing narrowly on single disease targets, the portfolio takes a 360° approach and prioritizes innovative research that reveals how fundamental cellular processes interact across cell types and biological systems to drive neurodegeneration and resilience. This includes supporting early-career investigators and researchers entering the field from other disciplines to advance current hypotheses and define where the field is going next.
Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, is characterized by progressive synaptic and neuronal loss, amyloid-β deposition, hyperphosphorylated tau accumulation, and chronic neuroinflammation, traditionally attributed primarily to the innate immune system. Increasing evidence, however, implicates the adaptive immune system as an active contributor to AD pathogenesis and progression. This emerging perspective has stimulated the development of immunomodulatory strategies aimed at mitigating cognitive decline and neuropathological hallmarks of the disease. In this review, we examine how adaptive immune responses change throughout the course of AD, integrating findings from both human studies and animal models while emphasizing the temporal dynamics of these alterations. We critically evaluate areas of consensus and controversy in the field, highlighting how differences in experimental models, disease stages, and methodological approaches contribute to divergent findings. Finally, we assess current therapeutic strategies targeting adaptive immunity, discussing their potential mechanisms of action and identifying key therapeutic windows and routes of administration that may maximize efficacy. By providing a comprehensive overview of adaptive immune involvement in AD, this review aims to inform the development of more precise and effective immunomodulatory interventions.
Neurodegenerative diseases are increasingly recognized as multicellular pathologies in which astrocytes serve as active determinants of disease onset and progression. Central to the regulatory role of astrocytes is the precise and dynamic control of brain lipid homeostasis. This review discusses a framework positioning astrocytic lipid metabolism as a key axis of both brain metabolic health and neurodegenerative processes. Under physiological conditions, astrocytes operate as the primary lipid metabolic hub, coordinating de novo cholesterol synthesis, APOE-mediated lipid transport, and the uptake and degradation of fatty acids. However, upon aging, chronic stress, and proteinopathies, these homeostatic programs undergo profound adaptation and remodeling. We detail how the breakdown of astrocytic lipid handling—driven by genetic risk factors such as APOE4 and manifesting as cholesterol dyshomeostasis, aberrant lipid droplet accumulation, impaired lipid turnover, and pro-inflammatory lipid signaling—transforms astrocytes into maladaptive reactive states and contributes to neurodegeneration. This metabolic rewiring not only deprives vulnerable neurons of essential metabolic and structural support but actively amplifies neuroinflammation and neurotoxicity. Finally, we consider therapeutic strategies aimed at restoring functional lipid flux and mitigating lipid-driven pathogenic signaling. By examining neurodegeneration through the lens of astrocytic lipid metabolism, we highlight novel conceptual paradigms for understanding neurodegeneration and emerging translational opportunities for disease interventions.
Active immunotherapy targeting amyloid-β (Aβ) represents a promising strategy for preventing Alzheimer’s disease (AD) in cognitively normal individuals at risk, referred to as the preclinical AD population. However, all Aβ vaccines tested so far in people with disease have faced significant challenges, primarily due to inadequate immunogenicity and insufficient antibody titers required to clear, reduce, or slow amyloid pathology. AV-1959R is a new generation MultiTEP-based Aβ vaccine specifically designed to overcome self-tolerance, provide broad T helper cell support, avoid the activation of Aβ-specific T cells, and elicit high levels of antibodies that selectively target pathological Aβ species in 100
The glymphatic system facilitates cerebrospinal fluid–interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer’s disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear. Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast–enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity. PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent. Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.
Diabetic retinopathy (DR), a leading cause of vision loss in working-age adults, is increasingly recognized as a combination of neurodegenerative and microvascular disease of the retina. Its pathological mechanism is complex, involving the regulation of multiple processes such as abnormal neovascularization, nerve damage, oxidative stress, and chronic inflammation. As a key molecular mechanism for regulating protein function, post-translational modifications (PTMs) can dynamically modulate the activity and function of core cells (including retinal endothelial cells, Müller cells, and pericytes) and related signaling molecules including various forms (e.g., phosphorylation, glycosylation, acetylation, methylation, ubiquitination, and SUMOylation), thereby deeply participating in the pathological progression of DR. In addition, PTMs play a crucial role in the regulating signaling pathways, including PI3K/Akt, MAPK, AMPK, NF-κB and JAK/STAT, in the development of DR. Moreover, increasing evidence demonstrates that targeting PTMs with small molecules, either as inhibitors or activators, can reverse protein misfolding and preserve neuroretinal integrity to halt the progression of DR. This review systematically summarizes the variation characteristics of different types of PTMs in DR, analyzes the involvement of PTMs on signaling cascade and cellular processes, reviews the association between ageing and PTMs, and sorts out the research progress of PTMs as potential diagnostic biomarkers and neuroprotective therapeutic targets for DR. It aims to offer a theoretical foundation for in-depth understanding of DR pathogenesis and the development of novel prevention and treatment strategies.
X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, encoding a peroxisomal membrane transporter required for the import of very-long-chain fatty acids (VLCFA) into peroxisomes for degradation. ABCD1 deficiency leads to VLCFA accumulation in plasma and tissues. The resulting disease has a highly variable clinical presentation. In males, this manifests as cerebral demyelination, progressive myelopathy, and adrenal insufficiency, alone or in combination. Women predominantly develop myelopathy, while cerebral disease and adrenal insufficiency are rare, occurring almost exclusively in cases of extreme X-inactivation skewing toward the mutant allele. The lipid-mediated mechanisms linking VLCFA accumulation to tissue-specific pathology remain incompletely understood. Here, we review evidence that VLCFA-containing complex lipids, rather than free VLCFAs alone, are central mediators of tissue-specific pathology in ALD and discuss the therapeutic implications of this lipid-centric perspective. VLCFAs are incorporated into a broad range of complex lipids, including phosphatidylcholines, lysophosphatidylcholines, cholesterol esters, triacylglycerols, sphingomyelins, ceramides, and plasmalogens. The degree of lipid dysregulation increases with acyl chain length and saturation. VLCFA-containing lipid species correlate with disease severity across all clinical phenotypes. In the brain, VLCFA-containing phosphatidylcholines accumulate before demyelination onset, cholesterol ester accumulation is associated with neuroinflammatory cascades, and plasmalogen depletion reflects early oxidative damage. In the spinal cord, VLCFA-containing myelin lipids are associated with non-inflammatory axonopathy, mitochondrial dysfunction, and microglial phagocytic activation. In the adrenal gland, VLCFA accumulation in cholesterol ester-rich lipid droplets impairs ACTH receptor signaling and sequesters cholesterol from steroidogenic pathways. Enzymatic regulators of VLCFA homeostasis, including ELOVL1, SCD1, and the omega-oxidation enzymes CYP4F2 and CYP4F3B, are potential therapeutic targets for substrate reduction. Plasma VLCFA-lipid profiles correlate with disease severity across all affected tissues, positioning lipidomic profiling as a potential clinical instrument for risk stratification and treatment monitoring. Secondary lipid mediators amplify primary VLCFA toxicity through distinct, cell-type-specific pathways. The near-exclusive occurrence of cerebral ALD and adrenal insufficiency in women with extreme X-inactivation skewing suggests that partial reduction of the VLCFA lipid burden, rather than complete normalization, may be sufficient to prevent severe disease manifestations. This has direct implications for substrate-reduction therapy development.
Passive immunotherapy targeting amyloid-β (Aβ) has emerged as a major therapeutic strategy for Alzheimer’s disease (AD), yet its clinical benefits remain modest and are frequently accompanied by vascular adverse events such as amyloid-related imaging abnormalities (ARIA). While the removal of extracellular Aβ plaques is associated with therapeutic efficacy, accumulating evidence suggests that additional cellular and vascular mechanisms may also contribute to complementary therapeutic outcomes alongside plaque removal. Recent studies show that Aβ antibodies are broadly distributed within the brain and interact with multiple neural and immune cell populations, rather than being limited to Aβ plaques. These observations support an expanded view of passive Aβ immunotherapy as a multicellular coordinated clearance process. Aβ antibodies engage diverse cellular and anatomical compartments, including neurons, glial cells, perivascular macrophages, peripheral immune cells, and meningeal lymphatic pathways, thereby influencing Aβ dynamics across intracellular and extracellular pools. Within this framework, therapeutic outcomes are influenced not only by plaque clearance but also by interactions between Aβ antibodies and cellular and anatomical compartments that regulate Aβ clearance and treatment-associated vascular response. This perspective may help explain variability in clinical efficacy and the emergence of vascular side effects, while also providing additional considerations for optimizing Aβ antibody design and therapeutic strategies.
Zhang et al. reveal that astrocytic PAD2-mediated citrullination of vimentin drives a TLR4-dependent pro-inflammatory loop in microglia, linking glial crosstalk to impaired amyloid clearance and identifying a potential therapeutic and biomarker pathway in Alzheimer’s disease.
TDP-43 proteinopathy coexists with tauopathy in a variety of neurodegenerative disorders, including Alzheimer's Disease (AD) and AD related dementia (ADRD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. Loss of TDP-43 splicing repression occurring during the early stage of neurodegenerative disease suggests that such loss could facilitate the pathological conversion of tau. Here, we report that TDP-43 loss-of-function (LOF) in forebrain neurons (Tau4R; CaMKII-CreER; Tardbpf/f mice) exacerbates tauopathy-dependent brain atrophy is associated with vulnerable neurons sensitive to caspase 3-dependent cleavage of endogenous tau. We demonstrate that TDP-43 LOF in human iPSC-derived cortical neurons promotes TDP-43 dependent cryptic splicing which precedes caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER; Tardbpf/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed correlates with caspase 3-dependent tau cleavage, accelerated tauopathy and the loss of vulnerable neurons deficient in TDP-43. Together, these results strongly support the view that TDP-43 dysfunction exacerbates tauopathy-dependent brain atrophy by promoting caspase 3-dependent endoproteolysis of tau, disclosing novel mechanistic insights and therapeutic targets for human tauopathies harboring the co-pathology of TDP-43.
Skin biopsy is a promising diagnostic tool for the in vivo identification of Parkinson’s disease and other α-synucleinopathies. However, despite increasing adoption, methodological variability exists among different laboratories applying this technique. To move toward a formal standardized protocol, leading experts in the field convened for a meeting focused on discussing and harmonizing the main methodological differences. The outcome of this meeting was a consensus-based skin biopsy protocol, which is here presented. A formal expert opinion conference was held on November 15–16, 2024, at the IRCCS Institute of Neurological Sciences of Bologna (Italy). The consensus was reached by using a Question Answer format following the PICO (Population, Intervention, Comparison, Outcome) methodology. An online Delphi survey was then performed based on the contrasting issues raised during the meeting. Unanimous consensus was reached on key elements, including the skin biopsy technique, choice of fixative, use of a cryostat, staining method for phosphorylated α-synuclein (p-α-syn), use of high-power fluorescence microscope, co-localization of p-α-syn with neuronal or glial markers, and high-magnification analysis. Additional agreement, achieved through the Delphi method, concerned specific procedural parameters such as the number of samples and section thickness, punch diameter, preferred biopsy sites in cases of asymmetric motor involvement, quantitative methods for assessing p-α-syn load, and use of p-α-syn as the optimal marker for identifying misfolded α-synuclein in the skin. Conclusions We have developed a consensus-based protocol for the detection of p-α-syn in skin samples from patients with suspected α-synucleinopathies, with the aim of promoting standardization, a broader adoption of the method, and its translation into clinical practice.
Abstract Our meta-analysis demonstrates that the risk effect of APOE-e4*4 relative to APOE-e3*3 for Alzheimer’s disease in the Japanese population is approximately 12–15-fold, comparable to that reported in Caucasian populations, rather than greater than 20-fold as previously reported.
Neutrophil Extracellular Traps (NETs) are web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils, which play a critical role in modulating neutrophil-mediated immune responses. Initially recognized for their role in host defense, NETs function as “molecular traps” that rapidly ensnare pathogens. They then achieve efficient clearance by directly degrading virulence factors through the action of associated antimicrobial proteins. However, the functions of NETs extend beyond immune defense. Dysregulation of NETs in pathological conditions can lead to detrimental effects. Recent studies have highlighted the importance of aberrant NET formation and impaired clearance in the pathogenesis of central nervous system (CNS) diseases, making them a field hotspot. In view of this, we discuss NETs, the structural characteristics and diverse generation patterns of NETs, and clarify how neutrophils cross the blood-brain barrier (BBB) to enter the CNS. We also explore triggers of NETosis within the brain, such as oxidative stress and inflammatory mediators. Furthermore, we analyze the pathological contributions of NETs to a range of CNS disorders, including stroke, traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), Alzheimer’s disease (AD), multiple sclerosis (MS), etc. Finally, we summarize emerging neuroprotective strategies that target NETs, highlighting advances in interventions designed to inhibit NET formation or promote their degradation. By synthesizing current evidence, this review aims to uncover the mysterious veil of NETs in neurological diseases and to offer new insights for understanding disease mechanisms and developing targeted therapeutic approaches.
Abstract Background There are no available treatments to halt or slow the progression of cerebral amyloid angiopathy (CAA), a disease neuropathologically characterized by the deposition of amyloid-β (Aβ) within the walls of the cerebrovasculature. Recently a novel therapeutic strategy has been described, targeting non-lipidated ApoE4 that co-deposits with Aβ, resulting in lower levels of Aβ across the brain. To understand the therapeutic potential for patients with CAA, we sought to determine if this global reduction in Aβ deposits corresponds to the active removal of existing aggregates in the vasculature and if so, whether this may improve vascular function over time. Methods Cranial windows were implanted in 9-10-month-old 5xFAD mice expressing human APOE4 to facilitate chronic, unanesthetized imaging using in vivo multiphoton microscopy. Mice were treated weekly with anti-ApoE4 immunotherapy (HAE-4) or control IgG (50 mg/kg). Parenchymal and vascular Aβ burden as well as vascular function were measured in vivo before and during treatment. Post-mortem brains were assessed for CAA, parenchymal Aβ plaques and iron deposits. In a separate study, 5xFAD mice were treated with weekly HAE-4 or control IgG with the same doses of antibodies from 8 to 10 months of age in the absence of cranial windows. Results Treatment with HAE-4 resulted in reduction of total Aβ plaque area post-mortem in mice and shrinkage of existing smaller plaques imaged with in vivo multiphoton microscopy. Vascular fibrillar Aβ under the cranial window conversely increased over time either with or without HAE-4 treatment and there was no treatment-associated improvement in vascular function in cortical arterioles in the areas measured in vivo. There was no evidence of hemorrhagic events linked to treatment, however there was significant immune cell activation. In 5xFAD mice treated without a cranial window, there was a reduction in plaques and CAA as previously described in HAE-4 vs. control treated mice. Conclusions Anti-ApoE4 immunotherapy, as shown previously, decreased the overall amount of Aβ. It also appeared to remove some existing plaque Aβ without measurable effects on vascular fibrillar Aβ deposits or vascular function in areas measured in vivo under a cranial window. The absence of treatment-associated hemorrhagic events may offer a comparative advantage relative to anti-Aβ immunotherapy.
The meningeal lymphatic system has recently emerged as a critical regulator of brain homeostasis, facilitating cerebrospinal fluid drainage, metabolic waste clearance, and immune cell trafficking. Accumulating evidence now implicates meningeal lymphatic dysfunction as a pivotal contributor to the pathogenesis of Alzheimer’s disease (AD). This review critically evaluates current neuroimaging techniques for assessing meningeal lymphatic function in humans, highlighting their technical limitations in capturing dynamic pathological changes specific to AD. We summarize recent advances demonstrating that meningeal lymphatic impairment exacerbates key AD hallmarks—including amyloid-β (Aβ) and tau deposition, neuroimmune dysregulation, and myelin degradation—collectively accelerating disease progression. Building on these insights, we systematically analyse emerging therapeutic strategies aimed at enhancing meningeal lymphatic function, such as pharmacological approaches (e.g., vascular endothelial growth factor C (VEGF-C)-mediated lymphangiogenesis), physical interventions (e.g., transcranial photobiomodulation), and surgical techniques (e.g., cervical lymphaticovenous anastomosis). However, significant challenges remain, including the scarcity of direct human evidence linking meningeal lymphatic dysfunction to AD and the lack of standardized, noninvasive assessment tools. To address these gaps, we propose future fundamental and clinical research directions for meningeal lymphatic vessels and AD. By bridging mechanistic insights with translational applications, this review highlights the role of the meningeal lymphatic system as a promising yet underexplored target for AD modification.
