Alzheimer's disease (AD) is marked by amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation. The β-site APP cleaving enzyme 1 (BACE1) is a key driver of Aβ production, while the NLRP3 inflammasome mediates microglial inflammatory responses. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase, is upregulated in AD, yet its role in disease mechanisms remains unclear. Here, we show that HDAC6 promotes BACE1 protein stability through direct deacetylation of its C-terminal lysine (K501), thereby increasing Aβ production. HDAC6 also facilitated NLRP3 inflammasome activation in microglia, increasing IL-1β production in a catalytic domain-dependent manner. HDAC6 deficiency in 5xFAD mice reduced BACE1 accumulation, Aβ deposition, ASC speck formation, and IL-1β levels, accompanied by improved cognitive performance. Transcriptomic profiling further revealed downregulation of disease-associated microglial and neurotoxic astrocyte signatures alongside enrichment of synaptic pathways. These findings establish HDAC6 as a dual regulator of Aβ production and neuroinflammation, highlighting it as a promising therapeutic target in AD.

The rapid rise of large language models has fuelled speculation about eventual artificial general intelligence. Winner of the Brain Essay Competition 2025, Alex Gwyn O’Hare considers whether it is technologically feasible for machines to achieve human-level intelligence, and philosophically plausible for them to possess consciousness.

Visual field loss is a common consequence of stroke and manifests in approximatively one-third of patients in the chronic stage. Such loss can significantly impact daily life activities, compromising tasks such as reading, navigating or driving. Although slow and labour intensive, evidence suggests that early interventions with tailored rehabilitation programmes might stimulate visual recovery and improve quality of life in stroke survivors.To enhance the effects of such rehabilitation programmes, we designed a novel, non-invasive, pathway-specific, physiology-inspired cross-frequency brain stimulation protocol, where complex oscillatory signal integration was inferred from phase–amplitude coupling of oscillatory signals between the primary visual cortex and the motion-sensitive medio-temporal area. Sixteen stroke patients were enrolled in a double-blind, randomized, cross-over trial, during which they performed two blocks of 10 daily training sessions of a direction discrimination task, combined with one of the two cross-frequency transcranial alternative brain stimulation (cf-tACS versus control cf-tACS) conditions.We found that the cf-tACS condition promoting feedforward visual inputs to the medio-temporal area significantly enhanced motion discrimination performance and shifted visual field borders (i.e. through localized enlargement of isopters). Behavioural improvements associated with a change in oscillatory activity within motion processing pathways were proportional to the amount of residual structural fibres along these pathways and perilesional primary visual cortex activity. In sum, we report, for the first time, that cf-tACS, a novel, pathway-specific, physiology-inspired brain stimulation approach, is able to boost the efficacy of perceptual training, restoring visual motion processing and reducing the severity of visual impairments in adult stroke patients.

Jean-Martin Charcot was born in Paris on 29 November 1825. To mark the bicentenary of his birth, the International Society for the History of the Neurosciences held a meeting in July 2025 at the Brain Institute in Paris. AJ Lees discusses the event and reflects on how Charcot’s scientific legacy continues to shape neurology today.

Pro-inflammatory T-helper 17 (Th17) cells are of vital importance in human autoimmune diseases such as multiple sclerosis (MS). Due to differentiation and functional plasticity, Th17 cells are able to produce a variety of pro-inflammatory cytokines such as interleukin (IL)-17A, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), and modulation of Th17 cell activities represents a desirable tool for disease-modifying treatment. Here, we aimed to understand the role of the surface molecule CD5 and its intracellular interaction partner casein kinase 2 (CK2) in human Th17 effector function as well as their role in multiple sclerosis.We performed targeted single-cell RNA sequencing from CSF obtained from people with multiple sclerosis and non-inflammatory neurological diseases, and high-sensitivity proteomic analysis of serum and CSF from 114 people with multiple sclerosis by using a proximity extension assay (PEA) together with functional investigations on CD4+ memory T cells differentiated into a Th17-polarized phenotype.Blockade of CD5 reduced the production of IL-17A, IFN-γ and GM-CSF by Th17-polarized cells without affecting proliferation. In comparison, blockade of its intracellular interaction partner CK2 exerted partly similar effects with a decrease in IL-17A and GM-CSF production but also impaired T cell proliferation. Both blocking agents resulted in a decreased phosphorylation of the downstream signalling molecule STAT3. The CD5 targeting treatment was able to abolish cytotoxic effects caused by Th17-polarized cells. Importantly, transcriptomic and proteomic analysis showed that CD5 expression correlates with an inflammatory immune profile in multiple sclerosis in serum as well as CSF.Our study highlights the importance of the CD5-CK2-STAT3 signalling axis for inflammatory responses of human Th17-polarized cells. Since in humans CD5 expression correlates with inflammation and cellular injury, targeting the CD5 signalling pathway provides future therapeutic opportunities for—among other diseases—multiple sclerosis.

The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression.In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns.Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions.Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

Parkinson's disease is a common and debilitating neurodegenerative disorder characterized by motor slowing (bradykinesia), which is thought to arise mainly owing to nigrostriatal dopaminergic cell loss. Paradoxically, longitudinal changes in striatal dopamine are poorly related to the progression of bradykinesia, indicating that other pathophysiological mechanisms play a role. In line with this, cross-sectional studies have shown that more benign motor phenotypes of Parkinson's disease are characterized by increased activity in the parieto-premotor cortex, indicative of cerebral compensation. However, the role of cerebral compensation in disease progression remains unclear. Here, we used a longitudinal design to test the hypothesis that the clinical progression of bradykinesia in Parkinson's disease is related to a decline in compensatory parieto-premotor function, over and above worsening nigrostriatal cell loss.We used a validated action selection task in combination with functional MRI to measure motor- and selection-related brain activity relative to the most-affected hand in a large sample of 351 patients with Parkinson's disease (≤5 years disease duration) and 60 healthy control subjects. In addition, we used diffusion-weighted MRI to obtain structural indices of substantia nigra and cerebral cortex integrity. These measurements were acquired at baseline and at 2-year follow-up, enabling us to compare longitudinal changes in brain metrics between patients and controls and to investigate their relationships with clinical metrics of bradykinesia progression.Consistent with our hypothesis, we observed that bradykinesia progression was inversely related to longitudinal changes in selection-related dorsal premotor cortex activity, suggesting that faster loss of cortical compensation contributes to faster symptom worsening. Importantly, this relationship remained after adjusting for longitudinal changes in the functional and structural integrity of the nigrostriatal system, indicating that bradykinesia progression is determined uniquely by loss of cortical compensation. In group comparisons of longitudinal change, patients with Parkinson's disease showed an overall reduction in putamen activity, which did not decrease further over time, in combination with an acceleration of structural decline in the substantia nigra and the premotor cortex. Despite showing expected patterns of Parkinson's disease pathology, neither of these metrics was correlated with bradykinesia progression.We conclude that the progression of bradykinesia in Parkinson's disease is determined by longitudinal changes in compensatory premotor cortex function. This presents opportunities to develop new progression-slowing interventions that focus on preserving and enhancing cortical compensation.

Recent anatomical studies have shown that, compared to other primates, the human frontal pole (FP) contains a unique lateral subdivision (FPl). This area provides an important target for understanding the uniqueness of human intelligence. Paradoxically, patients with FP lesions often perform normally on standard neuropsychological tests, while experiencing problems in real-life or simulated situations.This paper aims to review the complex functions of the FPl that may account for the dysfunctions observed in these patients. First, we consider studies of FP lesion patients that reveal deficits in analogical reasoning and prospective memory. Second, we review, mainly based on neuroimaging and neurostimulation studies, the FPl’s involvement in exploratory decision making, information integration and the representation of abstract rules. We argue that these functions primarily stem from the FPl’s capacity to manage multiple sources of information and to reduce that information into simpler features for guiding behaviour. Finally, we propose a model of the FPl that emphasizes its role in decomposing high-dimensional information to enhance decision making processes in conjunction with connected regions, including the posterior cingulate cortex, anterior cingulate cortex, and dorsolateral prefrontal cortex.

Loss-of-function mutations in the transcription factor POU3F2 have been identified in individuals with neurodevelopmental disorders. To elucidate the mechanistic role of POU3F2 in human neurodevelopment, we induced POU3F2 disruption in human neural progenitor cells (NPCs). Mutation of POU3F2 in NPCs causes reduced baseline canonical Wnt signalling and decreased proliferation, resulting in premature specification of radial glia. Additionally, POU3F2 levels across genetically diverse NPCs significantly associate positively with baseline canonical Wnt signalling and negatively with markers of radial glia specification.Through a series of unbiased analyses, we show that SRY-box transcription factor 13 (SOX13) and activity dependent neuroprotector homeobox (ADNP) are transcriptional targets of POU3F2 which mediate POU3F2's effects on Wnt signalling in human NPCs. Finally, we describe five individuals with autism spectrum disorder that harbour loss-of-function mutations in POU3F2, enhancing the genetic evidence for its critical role in human neurodevelopment. Together, these studies define POU3F2 as an activator of canonical Wnt signalling and mechanistically link two high-confidence autism genes, ADNP and POU3F2, in the regulation of neurodevelopment.

Autism spectrum disorder is a complex neurodevelopmental disease characterized by altered cortical network excitability. Recent genetic studies have identified deep layer V cortical pyramidal neurons in the frontal cortex as central to autism pathophysiology, yet the cortical circuits, plasticity mechanisms and molecular signalling pathways involved remain poorly understood. Layer V pyramidal neurons consist of two main types with distinct functional roles: intratelencephalic neurons, which respond to low-frequency stimulation and project within the cortex and striatum, and pyramidal tract neurons, which are tuned to theta-frequency inputs and convey information to subcortical structures. Determining which of these two neuron types is more critical to autism pathophysiology and whether disruptions in their synaptic connectivity or intrinsic excitability contribute to autism-related dysfunctions would significantly advance our understanding of the disorder. Integrins, a family of cell adhesion molecules, are vital for neuronal function. The gene encoding β3 integrin (ITGB3) is genetically linked to autism spectrum disorder, with rare mutations identified in affected individuals, while Itgb3 knockout mice exhibit autism-like behaviours, including impaired social memory and increased grooming. However, it remains unclear why loss of β3 integrin is associated with autism spectrum disorder, how it disrupts cortical circuits, and which plasticity mechanisms and molecular pathways are involved.Here, we demonstrate that β3 integrin selectively regulates the excitability of pyramidal tract neurons in the medial prefrontal cortex. Using electrophysiology, proteomics and molecular approaches, we show that β3 integrin regulates the gain, adaptation and precision of action potential discharge by controlling the surface expression of Ca2+-activated SK2 channels. Genetic ablation of Itgb3 impaired intrinsic excitability and SK2 channel function in pyramidal tract neurons, with no effects in intratelencephalic neurons. Furthermore, we identified Tau, a protein traditionally linked to neurodegenerative diseases, as part of the SK2 channel interactome. Proteomic analyses revealed altered protein kinase A-dependent phosphorylation of Tau in Itgb3 knockout mice, while protein kinase A inhibition restored SK2 channel currents, thereby connecting phosphorylation changes to excitability deficits.Our findings expand the current mechanistic framework linking signalling pathway dysfunctions to cortical excitability deficits, highlighting the dysregulation of pyramidal tract neuron excitability as a core feature of autism pathophysiology and demonstrating the involvement of β3 integrin, SK2 channels, Tau and PKA in this process. Because pyramidal tract neurons serve as final integrators of cortical computations before relaying information outside the cortex, their impaired excitability may disrupt communication with subcortical targets, contributing to the complex pathophysiology of autism spectrum disorder.