Wendy Noble

Background: Lewy body diseases (LBD), encompassing Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), are characterised by pathological α-synuclein (αSyn) aggregation, glial dysfunction and a lack of disease-modifying therapies. Converging evidence from α-synucleinopathy models, human neurodegenerative tissue and purinergic target-engagement studies implicates the glial ATP-gated P2X7 receptor (P2X7R) as a potential regulator of inflammatory and proteostatic stress.Main body: This review evaluates P2X7R as a candidate danger-amplifying hub in LBD. We propose that αSyn-rich, ATP-enriched microenvironments may shift glial P2X7R signalling from surveillance and clearance towards maladaptive effector programmes involving excitotoxic vulnerability, NF-κB/MAPK activation, inflammasome engagement, autophagic-lysosomal dysfunction and altered extracellular vesicle biology. We further consider human post-mortem, positron emission tomography (PET) imaging and preclinical evidence, highlighting that direct LBD-specific evidence remains limited and that P2X7R should be interpreted as a context-dependent glial effector receptor rather than a generic marker of inflammation. Conclusions: This framework provides a testable model in which chronic P2X7R activation may contribute to non-cell-autonomous neuronal injury and impaired αSyn handling. P2X7R therefore represents a promising but incompletely validated therapeutic target in LBD. Future studies should prioritise human validation, PET-based disease staging, multicellular αSyn models with cell-type-specific P2RX7 manipulation, and biomarker strategies that distinguish receptor availability from functional target engagement.

Alzheimer’s disease (AD) is characterized by a decline in neuronal proteostasis that favours the accumulation of misfolded proteins. Molecular chaperones are essential to prevent protein aggregation and, although typically studied as intracellular proteins, chaperones can also be secreted with functions that remain to be elucidated. Here, we identify a mechanism by which astrocyte-secreted HSPB1 is internalized by neurons to increase neuronal proteostasis and prevent the aggregation of pathological tau. We characterized HSPB1 as an astrocytic protein that can also be acquired post-transcriptionally by neurons in AD brain and in culture. Upon internalization into the endolysosomal system through macropinocytosis, HSPB1 prevents lysosomal damage and promotes tau clearance, thereby positioning HSPB1 as a key protein in maintaining organelle and protein homeostasis across astrocyte-neuronal networks. This work identifies a mechanism by which astrocytes boost neuronal capacity to protect from protein aggregation in neurodegeneration.

Signalling between the ER and mitochondria regulates a number of key cellular functions that are damaged in frontotemporal dementia and related amyotrophic lateral sclerosis (FTD/ALS). This signalling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ER–mitochondria “tethering” proteins. A number of studies have shown that mutant genes which cause familial FTD/ALS disrupt the VAPB-PTPIP51 tethers and that this involves activation of GSK3β. TDP43 is one such mutant and altered TDP43 metabolism is central to FTD/ALS pathogenesis. Loss of Sigma-1 receptor function is also seen in FTD/ALS and there is evidence that Sigma-1 receptor agonists can repair damaged ER–mitochondria signalling. However, the underlying mechanisms are not properly understood. In this study, we show that the reference Sigma-1 receptor agonist PRE-084 stimulates VAPB-PTPIP51 binding and rescues FTD/ALS mutant TDP43-induced disruption to the VAPB-PTPIP51 interaction and linked ER–mitochondria Ca²⁺ delivery. We also show that these effects involve inhibition of the kinase GSK3β, a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that ANAVEX2-73, a further Sigma-1 receptor agonist which is in clinical trials for Alzheimer’s disease, also stimulates VAPB-PTPIP51 binding via GSK3β inhibition. Our findings provide novel insights into the mechanisms by which Sigma-1 receptor agonists influence defective ER–mitochondria signalling in FTD/ALS.

Tauopathies are characterized by the progressive accumulation of abnormal tau species, which disrupt the autophagy-lysosomal pathway (ALP), a critical system for degrading intracellular macromolecules and aggregated proteins, causing toxicity and cell death. This study investigates the impact of the N-terminally truncated Tau35 protein overexpression on proteolytic pathways, including effects on autophagy and endo-lysosomal processes. Using a Tau35 mouse model and SH-SY5Y cell lines stably expressing either the Tau35 fragment or full-length tau, we employed western blotting, proteomic analysis of lysosome-enriched brain fractions, proteolysis/endocytosis assays, and live-cell imaging with the lysotracker reporter to assess protein degradation and lysosomal function. Our findings identify early pathological changes in endo-lysosomal processes, including increased endocytosis, proteolytic dysfunction and lysosomal motility abnormalities, associated with Tau35-induced toxicity. This work extends previous research by providing new insights into the mechanisms of Tau35-induced neurotoxicity, offering a foundation for developing targeted therapeutic strategies to address tauopathies.

Recent studies indicate that gut microbiota may play a crucial role in cognitive function. Individuals with cognitive impairment tend to have fewer beneficial gut bacteria and lower microbial diversity. Therefore, gut microbiota could be a potential biomarker for cognitive vulnerability. Further research is needed to understand the mechanisms and lifestyle factors affecting both microbiota composition and cognitive health. While the direct impact of microbiota and diet on cognitive impairment remains unconfirmed, this area holds promise for developing new preventive and treatment strategies.

Summary: The templated misfolding of tau proteins accounts for tau pathology spread in Alzheimer’s disease (AD). Post-translational modifications, including phosphorylation at specific residues, are closely linked with tau seeding ability and clinical disease progression. Increasing evidence supports a contributing role for astrocytes in tau spread. This study demonstrates that tau aggregates from postmortem AD brain are internalized and processed by human astrocytes. Differences in the efficiency of tau internalization, clearance and/or seeding were noted, which may reflect molecular properties of tau. Notably, we observed a direct relationship between alterations in tau handling by astrocytes and astrocyte responses, which were evident in transcriptomic data. Dysregulated genes include several previously identified as upregulated in reactive astrocytes in AD brain, as well as being implicated in pathological tau clearance by autophagy and other pathways. The study provides new insights into the complex interplay between tau molecular diversity and astrocyte responses in AD.

The autophagy-lysosomal pathway plays a critical role in the clearance of tau protein aggregates that deposit in the brain in tauopathies, and defects in this system are associated with disease pathogenesis. Here, we report that expression of Tau35, a tauopathy-associated carboxy-terminal fragment of tau, leads to lipid accumulation in cell lines and primary cortical neurons. Our findings suggest that this is likely due to a deleterious block of autophagic clearance and lysosomal degradative capacity by Tau35. Notably, upon induction of autophagy by Torin 1, Tau35 inhibited nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosomal biogenesis. Both cell lines and primary cortical neurons expressing Tau35 also exhibited changes in endosomal protein expression. These findings implicate autophagic and endolysosomal dysfunction as key pathological mechanisms through which disease-associated tau fragments could lead to the development and progression of tauopathy.