Biology subjects

Boxer, A. L.

Publications and source records attributed to Boxer, A. L..

10 recordsLinked to original sources

bioRxiv2026

Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.

neuroscience↗

bioRxiv2025

Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype-specific, and severity-linked alterations

Developing new treatment strategies for frontotemporal dementia (FTD) and other forms of neurodegeneration requires biomarkers to monitor disease progression. Dysregulated brain lipid metabolism, particularly sphingolipids enriched in the nervous system, is a key feature of neurodegeneration. However, plasma lipids have been investigated less for their potential as biomarkers than brain imaging and serum proteins. Here we examined the plasma lipidomes of a cohort of heterozygous carriers of gene variants associated with autosomal dominant familial FTD (including GRN, C9orf72, and MAPT loci), comparing them with aged-matched controls. In general, FTD subjects exhibited increases in plasma levels of specific species of gangliosides (GM3(d18:1_16:0), GM3(d18:1_18:0), and GM3(d18:1_24:1)) and ceramide (Cer(d18:1_23:0)) and selected polyunsaturated triacylglycerols (TG). Other species of ceramides (Cer(d18:0_22:0)), phosphatidylethanolamine (PE(18:0_24:0)), and sphingomyelin (SM(38:0)) were reduced in plasma of FTD subjects. Levels of glucosylsphingosine (GlcSph(d18:1)) were elevated specifically in GRN carriers, SM(34:1) was reduced in C9orf72 carriers, and TG(16:0_18:1_20:3)) were decreased in MAPT variant carriers. Notably, the ganglioside GM3(d18:1_16:0) was consistently elevated across all FTD genetic subtypes. Furthermore, the levels of these lipids correlated with disease severity in FTD patients. Our findings suggest that specific plasma lipid changes, notably several sphingolipids, may be useful biomarkers for FTD disease or progression.

systems biology↗

bioRxiv2024

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia

Mutations in progranulin (GRN) cause frontotemporal dementia (GRN-FTD) due to deficiency of the pleiotropic protein progranulin. GRN-FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN-FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn-/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn-/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

neuroscience↗

bioRxiv2024

Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia

BackgroundFrontotemporal dementia (FTD) is the most common cause of early-onset dementia with 10-20% of cases caused by mutations in one of three genes: GRN, C9orf72, or MAPT. To effectively develop therapeutics for FTD, the identification and characterization of biomarkers to understand disease pathogenesis and evaluate the impact of specific therapeutic strategies on the target biology as well as the underlying disease pathology are essential. Moreover, tracking the longitudinal changes of these biomarkers throughout disease progression is crucial to discern their correlation with clinical manifestations for potential prognostic usage. MethodsWe conducted a comprehensive investigation of biomarkers indicative of lysosomal biology, glial cell activation, synaptic and neuronal health in cerebrospinal fluid (CSF) and plasma from non-carrier controls, sporadic FTD (symptomatic non-carriers) and symptomatic carriers of mutations in GRN, C9orf72, or MAPT, as well as asymptomatic GRN mutation carriers. We also assessed the longitudinal changes of biomarkers in GRN mutation carriers. Furthermore, we examined biomarker levels in disease impacted brain regions including middle temporal gyrus (MTG) and superior frontal gyrus (SFG) and disease-unaffected inferior occipital gyrus (IOG) from sporadic FTD and symptomatic GRN carriers. ResultsWe confirmed glucosylsphingosine (GlcSph), a lysosomal biomarker regulated by progranulin, was elevated in the plasma from GRN mutation carriers, both symptomatic and asymptomatic. GlcSph and other lysosomal biomarkers such as ganglioside GM2 and globoside GB3 were increased in the disease affected SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers, but not in the IOG, compared to the same brain regions from controls. The glial biomarkers GFAP in plasma and YKL40 in CSF were elevated in asymptomatic GRN carriers, and all symptomatic groups, except the symptomatic C9orf72 mutation group. YKL40 was also increased in SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers. Neuronal injury and degeneration biomarkers NfL in CSF and plasma, and UCHL1 in CSF were elevated in patients with all forms of FTD. Synaptic biomarkers NPTXR, NPTX1/2, and VGF were reduced in CSF from patients with all forms of FTD, with the most pronounced reductions observed in symptomatic MAPT mutation carriers. Furthermore, we demonstrated plasma NfL was significantly positively correlated with disease severity as measured by CDR+NACC FTLD{square}SB in genetic forms of FTD and CSF NPTXR was significantly negatively correlated with CDR+NACC FTLD{square}SB in symptomatic GRN and MAPT mutation carriers. ConclusionsIn conclusion, our comprehensive investigation replicated alterations in biofluid biomarkers indicative of lysosomal function, glial activation, synaptic and neuronal health across sporadic and genetic forms of FTD and unveiled novel insights into the dysregulation of these biomarkers within brain tissues from patients with GRN mutations. The observed correlations between biomarkers and disease severity open promising avenues for prognostic applications and for indicators of drug efficacy in clinical trials. Our data also implicated a complicated relationship between biofluid and tissue biomarker changes and future investigations should delve into the mechanistic underpinnings of these biomarkers, which will serve as a foundation for the development of targeted therapeutics for FTD.

neuroscience↗

bioRxiv2023

Atrophy-driven functional network collapse in neurodegenerative disease

Cognitive and behavioral deficits in Alzheimers disease (AD) and frontotemporal dementia (FTD) result from brain atrophy and altered functional connectivity. However, it is unclear how atrophy relates to functional connectivity disruptions across dementia subtypes and stages. We addressed this question using structural and functional MRI from 221 patients with AD (n=82), behavioral variant FTD (n=41), corticobasal syndrome (n=27), nonfluent (n=34) and semantic (n=37) variant primary progressive aphasia, and 100 cognitively normal individuals. Using partial least squares regression, we identified three principal structure-function components. The first component showed overall atrophy correlating with primary cortical hypo-connectivity and subcortical/association cortical hyper-connectivity. Components two and three linked focal syndrome-specific atrophy to peri-lesional hypo-connectivity and distal hyper-connectivity. Structural and functional component scores predicted global and domain-specific cognitive deficits. Anatomically, functional connectivity changes reflected alterations in specific brain activity gradients. Eigenmode analysis identified temporal phase and amplitude collapse as an explanation for atrophy-driven functional connectivity changes.

neuroscience↗

bioRxiv2022

Single-cell RNA-seq reveals alterations in peripheral CX3CR1 and nonclassical monocytes in familial tauopathy

BackgroundEmerging evidence from mouse models is beginning to elucidate the brains immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system. MethodsTo address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau. ResultsAnalysis of [~]181,000 individual PBMC transcriptomes from MAPT pathogenic variant carriers (n = 8) and healthy non-carrier controls (n = 8) demonstrated striking differential expression in monocytes and natural killer (NK) cells. We observed a marked reduction in the expression of CX3CR1 - the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models - in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia. We confirmed differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using droplet digital PCR as an orthogonal technique for quantitative validation. ConclusionsOur results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.

neuroscience↗

bioRxiv2022

Radiogenomics of C9orf72 expansion carriers reveals global transposable element de-repression and enables prediction of thalamic atrophy and clinical impairment

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread de-repression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used the FreeSurfer pipeline and its extensions to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78) on atrophy of thalamic nuclei. We also generated a novel, whole-blood RNA-seq dataset to determine the relationships between peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element, L1HS. L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from HRE carriers revealed atrophy of specific thalamic nuclei; demonstrated that C9orf72 levels relate to clinical severity; and identified marked de-repression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei. Significance StatementPathogenic repeat expansion in C9orf72 is the most frequent genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (C9-FTD/ALS). The clinical, neuroimaging, and pathological features of C9-FTD/ALS are well-characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we utilized a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements--genetic elements typically repressed in the human genome--in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.

neuroscience↗

bioRxiv2020

Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy

The genetic basis of variation in the rate of disease progression of primary tauopathies has not been determined. In two independent progressive supranuclear palsy cohorts, we show that common variation at the LRRK2 locus determines survival from motor symptom onset to death, possibly through regulation of gene expression. This links together genetic risk in alpha-synuclein and tau disorders, and suggests that modulation of proteostasis and neuro-inflammation by LRRK2 inhibitors may have a therapeutic role across disorders.

genetics↗

bioRxiv2019

Systems analysis of blood transcriptomes in dementia patients reveals an innate immune response shared across disorders

The role of peripheral inflammation in dementia is an important but complex topic. We present here the largest cohort of peripheral blood gene expression data ever assembled from patients with dementia and matching controls. Importantly, this cohort includes individuals from a diverse set of dementia disorders, including Alzheimers Disease (AD), mild cognitive impairment (MCI), and multiple disorders within the frontotemporal dementia (FTD) spectrum. We found strong transcriptional evidence of an innate immune inflammatory response, mediated by monocytes and neutrophils, in AD, MCI, and two FTD subtypes, PSP and nfvPPA. This transcriptional inflammatory response is enriched for genetic risk for AD, in part because it is also enriched for microglial genes, which have previously been implicated in AD risk. Finally, we show that this transcriptional response is strongly enriched for binding of the transcription factors PU.1 and RELA, which have previously been linked to AD risk and progression.

bioinformatics↗

bioRxiv2018

Tau Secretion and Propagation Is Regulated by p300/CBP via Autophagy-Lysosomal Pathway in Tauopathy

The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. Tau secretion from neurons is the first step in tau transmission, but little is known about the cellular mechanism. Here, we report that p300/CBP, the lysine acetyltransferase that acetylates tau and regulates its homeostasis and toxicity, serves as a key regulator of tau secretion by inhibiting the autophagy-lysosomal pathway (ALP). Increased p300/CBP activity was associated with impaired function of this pathway in a tau transgenic mouse model. p300/CBP hyperactivation increased tau secretion by blocking autophagic flux. Conversely, inhibiting p300/CBP genetically or pharmacologically promoted autophagic flux, and reduced tau accumulation, tau secretion, and tau propagation in fibril-induced tau spreading models in vitro and in vivo. Our findings show that p300/CBP-induced impairment in the ALP underlies excessive unconventional secretion and pathogenic spread of tau.

neuroscience↗