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The majority of patients with Alzheimer's disease (AD) exhibit aggregates of Trans-active response DNA binding protein 43 (TDP-43) in their hippocampus, which is associated with a more aggressive disease progression. The TDP-43 inclusions are commonly found in neurons, but also in astrocytes. The impact of the inclusions in astrocytes is less known. In the current study, we investigate the presence of phosphorylated TDP-43 (pTDP-43) inclusions in astrocytic endfeet and their potential association with blood-brain barrier (BBB) damage, glymphatic system dysfunction, and AD pathology. By staining postmortem hippocampal sections from AD patients and non-demented controls against TDP-43 and pTDP-43 together with the astrocytic markers glial fibrillary acidic protein (GFAP), astrocytic endfeet marker Aquaporin-4 (AQP4), and markers for BBB alterations (CD146) and leakiness (Immunoglobulin A), we demonstrate a close association between perivascular pTDP-43 or TDP-43 inclusions and GFAP or AQP4. These perivascular inclusions were more prominent in AD and correlated with the disease severity and loss of CD146 and AQP4. The findings indicate a relationship between pTDP-43 accumulation in astrocytic endfeet and BBB and glymphatic system dysfunction, which may contribute to the downstream pathological events seen in AD patients and the aggressive disease progression.

The levels of p-tau217 and p-tau231 in cerebrospinal fluid (CSF) are associated with early amyloid beta (Aß) changes in the brain, while the CSF levels of p-tau205 are foremost related to tau pathology in the later stages of the disease. To investigate if the three p-tau variants are found to the same degree in different tau structures and if their co-localization is affected by the diagnosis and presence of Aß plaques, we immunostained sections of the entorhinal cortex (EC) and inferior temporal gyrus (ITG) from non-demented controls (NC), patients with Alzheimer's disease (AD), and primary age-related tauopathy (PART) against p-tau217, p-tau231, and p-tau205 together with Methoxi-X04. An analysis using confocal microscopy showed that the co-localization variable, the Pearson correlation coefficient (PCC), was significantly higher between p-tau231 and p-tau205 in neurofibrillary tangles compared to neuropil threads and dystrophic neurites in plaques. The PCC value between all three p-tau variants in the neuropil threads was significantly lower in the ECs of patients with AD compared to the NC and in the ITGs of patients with AD, with a high Aß load compared to PART. The lowered value was associated with proportionally higher amounts of non-colocalized p-tau231 and p-tau217 compared to p-tau205, and the PCC values were negatively correlated with Aß and the tangle loads in patients with AD, but positively correlated with tangles in PART. These results suggest that the proportion of and co-localization between p-tau217, p-tau231, and p-tau205 are dependent on cellular localization and are altered in response to AD pathology in a spatial-temporal manner.

In men, reduced levels of testosterone are associated with the prevalence and progression of multiple sclerosis (MS), a chronic and disabling demyelinating disorder. Testosterone has been shown to promote myelin repair. Here, we demonstrate that the cooperation between testosterone and CXCR4 signaling involving astrocytes is required for myelin regeneration after focal demyelination produced in the ventral mouse spinal cord by the infusion of lysolecithin. The testosterone-dependent remyelination of axons by oligodendrocytes was accompanied by an increase in astrocytes expressing CXCR4, its ligand CXCL12 and the androgen receptor (AR) within the demyelinated area. Depriving males of their testosterone or pharmacological inhibition of CXCR4, with the selective antagonist AMD3100, prevented the appearance of astrocytes expressing CXCR4, CXCL12 and AR within the demyelinated area and the concomitant recruitment of myelin forming oligodendrocytes. Conditional genetic ablation of either CXCR4 or AR in astrocytes also completely blocked the formation of new myelin by oligodendrocytes. Interestingly, the gain of function mutation in CXCR4 causing WHIM syndrome allows remyelination to take place, even in the absence of testosterone, but its potentiating effects remained observable. After testosterone deprivation or CXCR4 inhibition, the absence of astrocytes within the demyelinated area led to the incursion of Schwann cells, most likely derived from spinal nerves, and the formation of peripheral nerve type myelin. In patients with progressive MS, astrocytes expressing CXCR4 and AR surrounded myelin lesions, and their presence opposed the incursion of Schwann cells. These results highlight a mechanism of promyelinating testosterone signaling and the importance of normalizing its levels in combined myelin repair therapies.

The islet amyloid polypeptide (IAPP), a pancreas-produced peptide, has beneficial functions in its monomeric form. However, IAPP aggregates, related to type 2 diabetes mellitus (T2DM), are toxic not only for the pancreas, but also for the brain. In the latter, IAPP is often found in vessels, where it is highly toxic for pericytes, mural cells that have contractile properties and regulate capillary blood flow. In the current study, we use a microvasculature model, where human brain vascular pericytes (HBVP) are co-cultured together with human cerebral microvascular endothelial cells, to demonstrate that IAPP oligomers (oIAPP) alter the morphology and contractility of HBVP. Contraction and relaxation of HBVP was verified using the vasoconstrictor sphingosine-1-phosphate (S1P) and vasodilator Y27632, where the former increased, and the latter decreased, the number of HBVP with round morphology. Increased number of round HBVP was also seen after oIAPP stimulation, and the effect was reverted by the IAPP analogue pramlintide, Y27632, and the myosin inhibitor blebbistatin. Inhibition of the IAPP receptor with the antagonist AC187 only reverted IAPP effects partially. Finally, we demonstrate by immunostaining of human brain tissue against laminin that individuals with high amount of brain IAPP levels show significantly lower capillary diameter and altered mural cell morphology compared to individuals with low brain IAPP levels. These results indicate that HBVP, in an in vitro model of microvasculature, respond morphologically to vasoconstrictors, dilators, and myosin inhibitors. They also suggest that oIAPP induces contraction of these mural cells and that pramlintide can reverse such contraction.

Movement disorders (MD) have been linked to degeneration of the substantia nigra (SN) in Parkinson's disease and include bradykinesia, rigidity, and tremor. They are also present in frontotemporal dementia (FTD), where MD have been linked to frontotemporal lobar degeneration with tau pathology (FTLD-tau). Although MD can also occur in FTLD with TDP-43 pathology (FTLD-TDP), the local pathology in the SN of FTLD-TDP patients with MD is currently unexplored. The aims of this study are to characterize the frequency and the nature of MD in a cohort of FTLD-TDP brain donors and to investigate the relationship between the presence of MD, the nigral neuronal loss, and the TDP-43 burden in the SN. From our cohort of FTLD-TDP patients (n = 53), we included 13 donors who presented with MD (FTLD-MD+), and nine age-sex matched donors without MD (FTLD-MD-) for whom the SN was available. In these donors, the TDP-43 burden and the neuronal density in the SN were assessed with ImageJ and Qupath software. The results were compared between the two groups using T-test. We found that the TDP-43 burden in the SN was higher in FTLD-MD+ (mean 3,43%, SD ± 2,7) compared to FTLD-MD- (mean 1,21%, SD ± 0,67) (p = 0,04), while no significant difference in nigral neuronal density was found between the groups (p = 0,09). 17% of FTLD-TDP patients developed MD, which present as symmetric akinetic-rigid parkinsonism or CBS. Given the absence of a significant nigral neuronal cell loss, TDP-43 induced neuronal dysfunction could be sufficient to cause MD.

INTRODUCTION: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals-are they resilient, or resistant to AD-associated neuropathologies?METHODS: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and CERAD (neuritic plaque) scores with cognitive performance close to death as determined by Mini-Mental State Examination (MMSE) scores. We assessed centenarian brains against 2131 brains from AD patients, non-AD demented, and non-demented individuals in an age continuum ranging from 16 to 100+ years.RESULTS: With age, brains from non-demented individuals reached the NIA and Braak stages observed in AD patients, while CERAD scores remained lower. In centenarians, NIA stages varied (22.4% were the highest stage 3), Braak stages rarely exceeded stage IV (5.9% were V), and CERAD scores rarely exceeded 2 (4.7% were 3); within these distributions, we observed no correlation with the MMSE (NIA: P = 0.60; Braak: P = 0.08; CERAD: P = 0.16).DISCUSSION: Cognitive health can be maintained despite the accumulation of high levels of AD-related neuropathological substrates.HIGHLIGHTS: Cognitively healthy elderly have AD neuropathology levels similar to AD patients. AD neuropathology loads do not correlate with cognitive performance in centenarians. Some centenarians are resilient to the highest levels of AD neuropathology.

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Beside the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study is to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from the Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-beta, and alpha-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local FDR threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-beta (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-beta burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of alpha-synuclein co-pathology in the substantia nigra

The brain requires efficient information transfer between neurons and between large-scale brain regions. Brain connectivity follows predictable organizational principles: at the cellular level, larger supragranular pyramidal neurons have larger, more branched dendritic trees, more synapses, and perform more complex computations; at the macroscale, region-to-region connections display a diverse architecture with highly-connected hub-areas facilitating complex information integration and computation. Here, we explore the hypothesis that branching structure of large-scale region-to-region connectivity follows similar organizational principles as the neuronal scale. We examine microscale connectivity of basal dendritic trees of supragranular pyramidal neurons (300+) across ten cortical areas in five human donor brains (1M/4F). Dendritic complexity was quantified as number of branch points, tree length, spine count, spine density and overall branching complexity. High-resolution diffusion-weighted MRI was used to construct 'white matter trees' of cortico-cortical wiring. Examining complexity of the resulting white matter trees using the same measures as for dendritic trees shows heteromodal association areas to have larger, more complex white matter trees than primary areas (p<0.0001) and macroscale complexity to run in parallel with microscale measures, in terms of number of inputs (r=0.677, p=0.032), branch points (r=0.790, p=0.006), tree length (r=0.664, p=0.036) and branching complexity (r=0.724, p=0.018). Our findings support the integrative theory that brain connectivity follows similar 'principles of connectivity' at neuronal and macroscale level, and provide a framework to study connectivity changes in brain conditions at multiple levels of organization.SIGNIFICANCE STATEMENTWithin the human brain, cortical areas are involved in a wide range of processes, requiring different levels of information integration and local computation. At the cellular level, the

Parkinson’s disease (PD) is a neurodegenerative disease linked with the loss of dopaminer-gic neurons in the brain region called substantia nigra and caused by unknown pathogenic mecha-nisms. Two currently recognized prominent features of PD are an inflammatory response manifested by glial reaction and T-cell infiltration, as well as the presence of various toxic mediators derived from activated glial cells. PD or parkinsonism has been described after infection with several different viruses and it has therefore been hypothesized that a viral infection might play a role in the pathogen-esis of the disease. We investigated formalin-fixed post-mortem brain tissue from 9 patients with Parkinson’s disease and 11 controls for the presence of Ljungan virus (LV) antigen using a polyclonal antibody against the capsid protein of this recently identified picornavirus with neurotropic proper-ties, suspected of being both a human and an animal pathogen. Evidence of viral antigen was found in 7 out of 9 Parkinson’s disease cases and in only 1 out of 11 controls (p = 0.005). The picornavirus antigen was present in dopamine-containing neurons of the substantia nigra. We propose that LV or an LV-related virus initiates the pathological process underlying sporadic PD. LV-related picornavirus antigen has also been reported in patients with Alzheimer’s disease. Potentially successful antiviral treatment in Alzheimer’s disease suggests a similar treatment for Parkinson's disease. Amanta-dine, originally developed as an antiviral drug against influenza infection, has also been used for symptomatic treatment of patients with PD for more than 50 years and is still commonly used by neurologists today. The fact that amantadine also has an antiviral effect on picornaviruses opens the question of this drug being re-evaluated as potential PD therapy in combination with other antiviral compounds directed against picornaviruses.

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Beside the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study is to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from the Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-beta, and alpha-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local FDR threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-beta (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-beta burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of alpha-synuclein co-pathology in the substantia nigra

AIMS: The loss of von Economo neurons (VENs) and GABA receptor subunit theta (GABRQ) containing neurons is linked to early changes in social-emotional cognition and is seen in frontotemporal dementia (FTD) due to C9orf72 repeat expansion. We investigate the vulnerability of VENs and GABRQ-expressing neurons in sporadic and genetic forms of FTD with different underlying molecular pathology and their association with the presence and severity of behavioural symptoms.METHODS: We quantified VENs and GABRQ-immunopositive neurons in the anterior cingulate cortex (ACC) in FTD with underlying TDP43 (FTLD-TDP) (n=34), tau (FTLD-tau) (n=24), or FUS (FTLD-FUS) (n=8) pathology, neurologically healthy controls (n=12) and Alzheimer's disease (AD) (n=7). Second, we quantified VENs and the GABRQ-expressing population in relation to presence of behavioural symptoms in the first years of disease onset.RESULTS: The number of VENs and GABRQ-expressing neurons and the ratio of VENs and GABRQ-expressing neurons over total Layer 5 neuronal population decreased in FTLD-TDP and FTLD-FUS, but not in FTLD-tau, compared to control and AD. The severity of early behavioural symptoms in all donors correlated with a lower VEN and GABRQ neuronal count.CONCLUSION: We show that in FTD, a loss of VENs together with GABRQ-expressing pyramidal neurons is associated with TDP43 and FUS pathology. No significant loss was found in donors with FTLD-tau pathology; however, this could be due to the specific MAPT mutation studied and small sporadic FTLD-tau sample size. Overall, we show the GABRQ-expressing population correlates with behavioural changes and suggest they are key in modulating behaviour in FTD.

Frontotemporal lobar degeneration with MAPT pathogenic variants (FTLD-MAPT) has heterogeneous tau pathological inclusions postmortem, consisting of three-repeat (3R) or four-repeat (4R) tau isoforms, or a combination (3R + 4R). Here, we studied grey matter tau burden, its relation to neuronal degeneration, and regional patterns of pathology in different isoform groups of FTLD-MAPT. We included 38 FTLD-MAPT autopsy cases with 10 different MAPT pathogenic variants, grouped based on predominant tau isoform(s). In up to eleven regions (ten cortical and one striatal), we quantified grey matter tau burden using digital histopathological analysis and assigned semi-quantitative ratings for neuronal degeneration (i.e. 0-4) and separate burden of glial and neuronal tau inclusions (i.e. 0-3). We used mixed modelling to compare pathology measures (1) across the entire cohort and (2) within isoform groups. In the total cohort, tau burden and neuronal degeneration were positively associated and most severe in the anterior temporal, anterior cingulate and transentorhinal cortices. Isoform groups showed distinctive features of tau burden and neuronal degeneration. Across all regions, the 3R isoform group had lower tau burden compared to the 4R group (p = 0.008), while at the same time showing more severe neuronal degeneration than the 4R group (p = 0.002). The 3R + 4R group had an intermediate profile with relatively high tau burden along with relatively severe neuronal degeneration. Neuronal tau inclusions were most frequent in the 4R group (p < 0.001 vs. 3R), while cortical glial tau inclusions were most frequent in the 3R + 4R and 4R groups (p ≤ 0.009 vs. 3R). Regionally, neuronal degeneration was consistently most severe in the anterior temporal cortex within each isoform group. In contrast, the regions with the highest tau burden differed in isoform groups (3R: striatum; 3R + 4R: striatum, inferior parietal lobule, middle frontal cortex, anterior cingulate cortex; 4R: tr

The brain requires efficient information transfer between neurons and large-scale brain regions. Brain connectivity follows predictable organizational principles. At the cellular level, larger supragranular pyramidal neurons have larger, more branched dendritic trees, more synapses, and perform more complex computations; at the macroscale, region-to-region connections display a diverse architecture with highly connected hub areas facilitating complex information integration and computation. Here, we explore the hypothesis that the branching structure of large-scale region-to-region connectivity follows similar organizational principles as the neuronal scale. We examine microscale connectivity of basal dendritic trees of supragranular pyramidal neurons (300+) across 10 cortical areas in five human donor brains (1 male, 4 female). Dendritic complexity was quantified as the number of branch points, tree length, spine count, spine density, and overall branching complexity. High-resolution diffusion-weighted MRI was used to construct white matter trees of corticocortical wiring. Examining complexity of the resulting white matter trees using the same measures as for dendritic trees shows heteromodal association areas to have larger, more complex white matter trees than primary areas (p < 0.0001) and macroscale complexity to run in parallel with microscale measures, in terms of number of inputs (r = 0.677, p = 0.032), branch points (r = 0.797, p = 0.006), tree length (r = 0.664, p = 0.036), and branching complexity (r = 0.724, p = 0.018). Our findings support the integrative theory that brain connectivity follows similar principles of connectivity at neuronal and macroscale levels and provide a framework to study connectivity changes in brain conditions at multiple levels of organization.SIGNIFICANCE STATEMENT Within the human brain, cortical areas are involved in a wide range of processes, requiring different levels of information integration and local computation.

Loss-of-function variants in the low-density lipoprotein receptor-related protein 10 (LRP10) gene have been associated with autosomal-dominant Parkinson’s disease (PD), PD dementia, and dementia with Lewy bodies (DLB). Moreover, LRP10 variants have been found in individuals diagnosed with progressive supranuclear palsy and amyotrophic lateral sclerosis. Despite this genetic evidence, little is known about the expression and function of LRP10 protein in the human brain under physiological or pathological conditions. To better understand how LRP10 variants lead to neurodegeneration, we first performed an in-depth characterisation of LRP10 expression in post-mortem brains and human-induced pluripotent stem cell (iPSC)-derived astrocytes and neurons from control subjects. In adult human brain, LRP10 is mainly expressed in astrocytes and neurovasculature but undetectable in neurons. Similarly, LRP10 is highly expressed in iPSC-derived astrocytes but cannot be observed in iPSC-derived neurons. In astrocytes, LRP10 is present at trans-Golgi network, plasma membrane, retromer, and early endosomes. Interestingly, LRP10 also partially co-localises and interacts with sortilin-related receptor 1 (SORL1). Furthermore, although LRP10 expression and localisation in the substantia nigra of most idiopathic PD and DLB patients and LRP10 variant carriers diagnosed with PD or DLB appeared unchanged compared to control subjects, significantly enlarged LRP10-positive vesicles were detected in a patient carrying the LRP10 p.Arg235Cys variant. Last, LRP10 was detected in Lewy bodies (LB) at late maturation stages in brains from idiopathic PD and DLB patients and in LRP10 variant carriers. In conclusion, high LRP10 expression in non-neuronal cells and undetectable levels in neurons of control subjects indicate that LRP10-mediated pathogenicity is initiated via cell non-autonomous mechanisms, potentially involving the interaction of LRP10 with SORL1 in vesicle trafficking pathways. Togeth

Aim: Identify grey- and white-matter-specific DNA-methylation differences between schizophrenia (SCZ) patients and controls in postmortem brain cortical tissue. Materials & methods: Grey and white matter were separated from postmortem brain tissue of the superior temporal and medial frontal gyrus from SCZ (n = 10) and control (n = 11) cases. Genome-wide DNA-methylation analysis was performed using the Infinium EPIC Methylation Array (Illumina, CA, USA). Results: Four differentially methylated regions associated with SCZ status and tissue type (grey vs white matter) were identified within or near KLF9, SFXN1, SPRED2 and ALS2CL genes. Gene-expression analysis showed differential expression of KLF9 and SFXN1 in SCZ. Conclusion: Our data show distinct differences in DNA methylation between grey and white matter that are unique to SCZ, providing new leads to unravel the pathogenesis of SCZ.

Although the right temporal variant frontotemporal dementia (rtvFTD) is characterised by distinct clinical and radiological features, its underlying histopathology remains elusive. Being considered a right-sided variant of semantic variant primary progressive aphasia (svPPA), TDP-43 type C pathology has been linked to the syndrome, but this has not been studied in detail in large cohorts. In this case report and systematic review, we report the autopsy results of five subjects diagnosed with rtvFTD from our cohort and 44 single rtvFTD subjects from the literature. Macroscopic pathological evaluation of the combined results revealed that rtvFTD demonstrated either a frontotemporal or temporal evolution, even if the degeneration started in the right temporal lobe initially. FTLD-TDP type C was the most common underlying pathology in rtvFTD, however, in 64% of rtvFTD, other underlying pathologies than FTLD-TDP type C were present, such as Tau-MAPT and FTLD-TDP type A and B. Additionally, accompanying motor neuron or corticospinal tract degeneration was observed in 28% of rtvFTD patients. Our results show that in contrast to the general assumption, rtvFTD might not be a pure FTLD-TDP type C disorder, unlike its left temporal counterpart svPPA. Large sample size pathological studies are warranted to understand the diverse pathologies of the right and left temporal variants of frontotemporal dementia.

A clinical syndrome with neuropsychiatric features of bvFTD without neuroimaging abnormalities and a lack of decline is a phenocopy of bvFTD (phFTD). Growing evidence suggests that psychological, psychiatric and environmental factors underlie phFTD. We describe a patient diagnosed with bvFTD prior to the revision of the diagnostic guidelines of FTD. Repeated neuroimaging was normal and there was no FTD pathology at autopsy, rejecting the diagnosis. We hypothesize on etiological factors that on hindsight might have played a role. This case report contributes to the understanding of phFTD and adds to the sparse literature of the postmortem assessment of phFTD.

Loss-of-function variants in the low-density lipoprotein receptor-related protein 10 (LRP10) gene have been associated with autosomal-dominant Parkinson's disease (PD), PD dementia, and dementia with Lewy bodies (DLB). Moreover, LRP10 variants have been found in individuals diagnosed with progressive supranuclear palsy and amyotrophic lateral sclerosis. Despite this genetic evidence, little is known about the expression and function of LRP10 protein in the human brain under physiological or pathological conditions. To better understand how LRP10 variants lead to neurodegeneration, we first performed an in-depth characterisation of LRP10 expression in post-mortem brains and human-induced pluripotent stem cell (iPSC)-derived astrocytes and neurons from control subjects. In adult human brain, LRP10 is mainly expressed in astrocytes and neurovasculature but undetectable in neurons. Similarly, LRP10 is highly expressed in iPSC-derived astrocytes but cannot be observed in iPSC-derived neurons. In astrocytes, LRP10 is present at trans-Golgi network, plasma membrane, retromer, and early endosomes. Interestingly, LRP10 also partially co-localises and interacts with sortilin-related receptor 1 (SORL1). Furthermore, although LRP10 expression and localisation in the substantia nigra of most idiopathic PD and DLB patients and LRP10 variant carriers diagnosed with PD or DLB appeared unchanged compared to control subjects, significantly enlarged LRP10-positive vesicles were detected in a patient carrying the LRP10 p.Arg235Cys variant. Last, LRP10 was detected in Lewy bodies (LB) at late maturation stages in brains from idiopathic PD and DLB patients and in LRP10 variant carriers. In conclusion, high LRP10 expression in non-neuronal cells and undetectable levels in neurons of control subjects indicate that LRP10-mediated pathogenicity is initiated via cell non-autonomous mechanisms, potentially involving the interaction of LRP10 with SORL1 in vesicle trafficking pathways. Togeth