Biomedical subjects

Stephen M Strittmatter

Publications and source records attributed to Stephen M Strittmatter.

At least 19 recordsLinked to original sources

PubMed2026

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female.

BackgroundAlzheimer's disease (AD), the most common age-related neurodegenerative disease, is closely associated with both amyloid-β plaque and neuroinflammation. Two thirds of AD patients are female, and they have a higher disease risk; women with AD have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration.ObjectiveThis study aimed to determine how sex difference induces structural brain changes and molecular cell vulnerabilities in AD, with a focus on identifying sex-specific transcriptional alterations and genetic risk factors.MethodsWe performed single nucleus RNA sequencing on postmortem brains from individuals with AD and age- and sex-matched controls, focusing on the middle temporal gyrus, a cortical brain region strongly affected by the disease, and integrated single nucleus RNA sequencing results with genome-wide association study (GWAS) data using cell type-specific enrichment and generalized gene-set analysis approaches. The analysis pipeline is provided with threshold information.ResultsWe identified a selectively vulnerable subpopulation of layer 2/3 excitatory neurons that were RORB-negative and CDH9-expressing in both males and females. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of AD brains differed between males and females. Integrating single cell transcriptomic data with results from GWAS, we identified MERTK genetic variation as a candidate novel risk factor for AD selectively in females.ConclusionsTaken together, our single cell atlas of middle temporal gyrus revealed a unique cellular-level view of sex-specific transcriptional changes in AD, illuminating GWAS identification of sex-specific AD genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of AD.

Alzheimer's disease↗

PubMed2023

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type and sex specificity of gene expression with novel genetic risk for MERTK in female.

Alzheimer's disease, the most common age-related neurodegenerative disease, is closely associated with both amyloid-ß plaque and neuroinflammation. Two thirds of Alzheimer's disease patients are females and they have a higher disease risk. Moreover, women with Alzheimer's disease have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration. To identify how sex difference induces structural brain changes, we performed unbiased massively parallel single nucleus RNA sequencing on Alzheimer's disease and control brains focusing on the middle temporal gyrus, a brain region strongly affected by the disease but not previously studied with these methods. We identified a subpopulation of selectively vulnerable layer 2/3 excitatory neurons that that were RORB-negative and CDH9-expressing. This vulnerability differs from that reported for other brain regions, but there was no detectable difference between male and female patterns in middle temporal gyrus samples. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of diseased brains differed between males and females. Combining single cell transcriptomic data with results from genome-wide association studies (GWAS), we identified MERTK genetic variation as a risk factor for Alzheimer's disease selectively in females. Taken together, our single cell dataset revealed a unique cellular-level view of sex-specific transcriptional changes in Alzheimer's disease, illuminating GWAS identification of sex-specific Alzheimer's risk genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of Alzheimer's disease.

Journal Article↗

PubMed2006

Characterization of myelin ligand complexes with neuronal Nogo-66 receptor family members.

Nogo, MAG, and OMgp are myelin-associated proteins that bind to a neuronal Nogo-66 receptor (NgR/NgR1) to limit axonal regeneration after central nervous system injury. Within Nogo-A, two separate domains are known interact with NgR1. NgR1 is the founding member of the three-member NgR family, whereas Nogo-A (RTN4A) belongs to a four-member reticulon family. Here, we systematically mapped the interactions between these superfamilies, demonstrating novel nanomolar interactions of RTN2 and RTN3 with NgR1. Because RTN3 is expressed in spinal cord white matter, it may have a role in myelin inhibition of axonal growth. Further analysis of the Nogo-A and NgR1 interactions revealed a novel third interaction site between the proteins, suggesting a trivalent Nogo-A interaction with NgR1. We also confirmed here that MAG binds to NgR2, but not to NgR3. Unexpectedly, we found that OMgp interacts with MAG with a higher affinity compared with NgR1. To better define how these multiple structurally distinct ligands bind to NgR1, we examined a series of Ala-substituted NgR1 mutants for ligand binding activity. We found that the core of the binding domain is centered in the middle of the concave surface of the NgR1 leucine-rich repeat domain and surrounded by differentially utilized residues. This detailed knowledge of the molecular interactions between NgR1 and its ligands is imperative when assessing options for development of NgR1-based therapeutics for central nervous system injuries.

Amino Acid Substitution↗

PubMed2006

Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer's transgenic mice.

The production and aggregation of cerebral amyloid-beta (Abeta) peptide are thought to play a causal role in Alzheimer's disease (AD). Previously, we found that the Nogo-66 receptor (NgR) interacts physically with both Abeta and the amyloid precursor protein (APP). The inverse correlation of Abeta levels with NgR levels within the brain may reflect regulation of Abeta production and/or Abeta clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated Abeta clearance in APPswe/PSEN-1deltaE9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15-28 aa of Abeta associate with specific surface-accessible patches on the leucine-rich repeat concave side of the solenoid structure of NgR. In transgenic mice, subcutaneous NgR(310)ecto-Fc treatment reduces brain Abeta plaque load while increasing the relative levels of serum Abeta. These changes in Abeta are correlated with improved spatial memory in the radial arm water maze. The benefits of peripheral NgR administration are evident when therapy is initiated after disease onset. Thus, the peripheral association of NgR(310)ecto-Fc with central Abeta residues provides an effective therapeutic approach for AD.

Alzheimer Disease↗

PubMed2006

The Nogo-Nogo receptor pathway limits a spectrum of adult CNS axonal growth.

The hypothesis that Nogo-A (Reticulon 4A) and Nogo-66 receptor (NgR1) limit adult CNS axonal growth after injury is supported by both in vitro experiments and in vivo pharmacological studies. However, genetic assessment of the role of Nogo-A in corticospinal tract (CST) axons after spinal cord dorsal hemisection has yielded conflicting results. CST regeneration is detected in homozygous nogo-ab(trap/trap) mice, but not in nogo-ab(atg/atg) mice. CST regeneration is also present after pharmacological NgR blockade, but not in ngr1(-/-) mice. To assess the nogo-ab(atg) and ngr1-null alleles for other axon growth phenotypes, we created unilateral pyramidotomies and monitored the uninjured CST. There is robust pyramidotomy-induced growth of nogo-ab(atg/atg) and ngr1(-/-) CST axons into denervated cervical gray matter. This fiber growth correlates with recovery of fine motor skill in the affected forelimb. Thus nogo-ab and ngr1 play a modulated role in limiting CNS axonal growth across a spectrum of different tracts in various lesion models.

Analysis of Variance↗

PubMed2006

Extracellular regulators of axonal growth in the adult central nervous system.

Robust axonal growth is required during development to establish neuronal connectivity. However, stable fibre patterns are necessary to maintain adult mammalian central nervous system (CNS) function. After adult CNS injury, factors that maintain axonal stability limit the recovery of function. Extracellular molecules play an important role in preserving the stability of the adult CNS axons and in restricting recovery from pathological damage. Adult axonal growth inhibitors include a group of proteins on the oligodendrocyte, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein and ephrin-B3, which interact with axonal receptors, such as NgR1 and EphA4. Extracellular proteoglycans containing chondroitin sulphates also inhibit axonal sprouting in the adult CNS, particularly at the sites of astroglial scar formation. Therapeutic perturbations of these extracellular axonal growth inhibitors and their receptors or signalling mechanisms provide a degree of axonal sprouting and regeneration in the adult CNS. After CNS injury, such interventions support a partial return of neurological function.

Animals↗

PubMed2006

Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells.

Nogo isoforms (Nogo-A and -B) have been implicated in regulating neural and cardiovascular functions, such as cell spreading and chemotaxis. Unlike the loop domain (Nogo-66) found in all Nogo isoforms that can interact with a neural-specific Nogo-66 receptor, the receptor for the amino terminus of Nogo-B that mediates vascular function is unknown. Here, we identify a previously uncharacterized Nogo-B receptor specific for the amino terminus of Nogo-B and show that Nogo-B receptor localizes with the ligand Nogo-B during VEGF and wound healing angiogenesis in vivo, mediates chemotaxis in a heterologous expression system and chemotaxis, and 3D tube formation in native endothelial cells. Thus, identification of this receptor may lead to the discovery of agonists or antagonists of this pathway to regulate vascular remodeling and angiogenesis.

Amino Acid Sequence↗

PubMed2006

RanBPM contributes to Semaphorin3A signaling through plexin-A receptors.

Secreted Semaphorin3A (Sema3A) proteins are known to act as diffusible and repellant axonal guidance cues during nervous system development. A receptor complex consisting of a Neuropilin and a Plexin-A mediates their effects. Plexin-A signal transduction has remained poorly defined despite the documented involvement of collapsin response mediator protein and molecule interacting with CasL proteins (MICALs) as mediators of Plexin-A activation. Here, we defined a domain of Plexin-A1 required for Sema3A signaling in a reconstituted environment and then searched for proteins interacting with this domain. RanBPM is shown to physically interact with Plexin-A1, and the RanBPM/Plexin complex is regulated by MICAL expression. Overexpression of RanBPM cooperates with PlexinA1 to reduce non-neuronal cell spreading and strongly inhibit axonal outgrowth in vitro and in vivo. A truncated RanBPM protein blocks Sema3A responsiveness in non-neuronal and neuronal cells. Suppression of RanBPM expression reduces Sema3A responsiveness. Thus, RanBPM is a mediator of Sema3A signaling through Plexin-A. RanBPM has the potential to link Plexin-A receptors to retrograde transport and microtubule function in axonal guidance.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition.

Pathophysiologic hypotheses for Alzheimer's disease (AD) are centered on the role of the amyloid plaque Abeta peptide and the mechanism of its derivation from the amyloid precursor protein (APP). As part of the disease process, an aberrant axonal sprouting response is known to occur near Abeta deposits. A Nogo to Nogo-66 receptor (NgR) pathway contributes to determining the ability of adult CNS axons to extend after traumatic injuries. Here, we consider the potential role of NgR mechanisms in AD. Both Nogo and NgR are mislocalized in AD brain samples. APP physically associates with the NgR. Overexpression of NgR decreases Abeta production in neuroblastoma culture, and targeted disruption of NgR expression increases transgenic mouse brain Abeta levels, Abeta plaque deposition, and dystrophic neurites. Infusion of a soluble NgR fragment reduces Abeta levels, amyloid plaque deposits, and dystrophic neurites in a mouse transgenic AD model. Changes in NgR level produce parallel changes in secreted APPalpha and Abeta, implicating NgR as a blocker of secretase processing of APP. The NgR provides a novel site for modifying the course of AD and highlights the role of axonal dysfunction in the disease.

Alzheimer Disease↗

PubMed2006

Delayed Nogo receptor therapy improves recovery from spinal cord contusion.

OBJECTIVE: Myelin-associated inhibitors play a role in limiting axonal growth in the adult central nervous system. Blocking these inhibitors may promote neurological recovery from spinal cord contusion. METHODS: The soluble Nogo-66 receptor (NgR(310)ecto-Fc) protein, which can neutralize three myelin inhibitors, was infused into rats after spinal cord contusion for 28 days. Treatment was initiated intrathecally at the time of injury or 3 days after injury by the intracerebroventricular route at a dose of 0.29 mg/kg/day. Recovery of locomotion and of axonal growth was assessed. Some animals received combination therapy with NgR(310)ecto-Fc plus rolipram, a cyclic adenosine monophosphate phosphodiesterase inhibitor. RESULTS: Seven weeks after spinal injury, the Basso-Beattie Bresnahan locomotor scores were significantly improved in the 3-day delayed NgR(310)ecto-Fc treatment group (9.5 +/- 0.7; n = 16) versus the vehicle-treated group, (6.75 +/- 0.7; n = 15) (p < or = 0.01, analysis of variance). The percentage of NgR(310)ecto-Fc-treated animals able to support their weight was twice that in the control group. Delayed therapy was as efficacious as acute therapy. Addition of rolipram did not alter recovery. The beneficial behavioral effects of NgR(310)ecto-Fc correlated with sprouting of raphespinal axons in the caudal spinal cord and of corticospinal axons in the rostral spinal cord. INTERPRETATION: NgR(310)ecto-Fc treatment improves outcome in a rodent model that closely mimicked human spinal cord injury.

Animals↗

PubMed2006

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat.

Axons show a poor regenerative capacity following traumatic central nervous system (CNS) injury, partly due to the expression of inhibitors of axonal outgrowth, of which Nogo-A is considered the most important. We evaluated the acute expression of Nogo-A, the Nogo-66 receptor (NgR) and the novel small proline-rich repeat protein 1A (SPRR1A, previously undetected in brain), following experimental lateral fluid percussion (FP) brain injury in rats. Immunofluorescence with antibodies against Nogo-A, NgR and SPRR1A was combined with antibodies against the neuronal markers NeuN and microtubule-associated protein (MAP)-2 and the oligodendrocyte marker RIP, while Western blot analysis was performed for Nogo-A and NgR. Brain injury produced a significant increase in Nogo-A expression in injured cortex, ipsilateral external capsule and reticular thalamus from days 1-7 post-injury (P < 0.05) compared to controls. Increased expression of Nogo-A was observed in both RIP- and NeuN positive (+) cells in the ipsilateral cortex, in NeuN (+) cells in the CA3 region of the hippocampus and reticular thalamus and in RIP (+) cells in white matter tracts. Alterations in NgR expression were not observed following traumatic brain injury (TBI). Brain injury increased the extent of SPRR1A expression in the ipsilateral cortex and the CA3 at all post-injury time-points in NeuN (+) cells. The marked increases in Nogo-A and SPRR1A in several important brain regions suggest that although inhibitors of axonal growth may be upregulated, the injured brain is also capable of expressing proteins promoting axonal outgrowth following TBI.

Animals↗

PubMed2006

Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury?

The precise wiring of the adult mammalian CNS originates during a period of stunning growth, guidance and plasticity that occurs during and shortly after development. When injured in adults, this intricate system fails to regenerate. Even when the obstacles to regeneration are cleared, growing adult CNS fibres usually remain misdirected and fail to reform functional connections. Here, we attempt to fill an important niche related to the topics of nervous system development and regeneration. We specifically contrast the difficulties faced by growing fibres within the adult context to the precise circuit-forming capabilities of developing fibres. In addition to focusing on methods to stimulate growth in the adult, we also expand on approaches to recapitulate development itself.

Animals↗

PubMed2005

Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor.

Monocular deprivation normally alters ocular dominance in the visual cortex only during a postnatal critical period (20 to 32 days postnatal in mice). We find that mutations in the Nogo-66 receptor (NgR) affect cessation of ocular dominance plasticity. In NgR-/- mice, plasticity during the critical period is normal, but it continues abnormally such that ocular dominance at 45 or 120 days postnatal is subject to the same plasticity as at juvenile ages. Thus, physiological NgR signaling from myelin-derived Nogo, MAG, and OMgp consolidates the neural circuitry established during experience-dependent plasticity. After pathological trauma, similar NgR signaling limits functional recovery and axonal regeneration.

Animals↗

PubMed2005

Nogo-A interacts with the Nogo-66 receptor through multiple sites to create an isoform-selective subnanomolar agonist.

Nogo is a myelin-derived protein that limits axonal regeneration after CNS injury. A short hydrophilic Nogo-66 loop between two hydrophobic domains of Nogo binds to a Nogo-66 receptor (NgR) to inhibit axonal outgrowth. Inhibition of axon outgrowth and cell spreading by a second Nogo domain, termed Amino-Nogo-A, is thought to be mediated by a distinct receptor complex. Here, we define a novel Nogo-A-specific domain in Amino-Nogo that binds to NgR with nanomolar affinity. This second domain of 24 amino acids does not alter cell spreading or axonal outgrowth. Fusion of the two NgR-binding Nogo-A domains creates a ligand with substantially enhanced affinity for NgR and converts a NgR antagonist peptide to an agonist. Thus, NgR activation by Nogo-A involves multiple sites of interaction between Nogo-A and NgR.

Alkaline Phosphatase↗

PubMed2005

Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury.

Axon growth after spinal injury is thought to be limited in part by myelin-derived proteins that act via the Nogo-66 Receptor (NgR). To test this hypothesis, we sought to study recovery from spinal cord injury (SCI) after inhibiting NgR transgenically with a soluble function-blocking NgR fragment. Glial fibrillary acidic protein (gfap) gene regulatory elements were used to generate mice that secrete NgR(310)ecto from astrocytes. After mid-thoracic dorsal over-hemisection injury, gfap::ngr(310)ecto mice exhibit enhanced raphespinal and corticospinal axonal sprouting into the lumbar spinal cord. Recovery of locomotion is improved in the gfap::ngr(310)ecto mice. These data indicate that the NgR ligands, Nogo-66, MAG, and OMgp, play a role in limiting axonal growth in the injured adult CNS and that NgR(310)ecto might provide a therapeutic means to promote recovery from SCI.

Animals↗

PubMed2005

Effect of combined treatment with methylprednisolone and soluble Nogo-66 receptor after rat spinal cord injury.

Methylprednisolone (MP) is a synthetic glucocorticoid used for the treatment of spinal cord injury (SCI). Soluble Nogo-66 receptor (NgR) ectodomain is a novel experimental therapy for SCI that promotes axonal regeneration by blocking the growth inhibitory effects of myelin constituents in the adult central nervous system. To evaluate the potential complementarity of these mechanistically distinct pharmacological reagents we compared their effects alone and in combination after thoracic (T7) dorsal hemisection in the rat. Treatment with an ecto-domain of the rat NgR (27-310) fused to a rat IgG [NgR(310)ecto-Fc] (50 microm intrathecal, 0.25 microL/h for 28 days) or MP alone (30 mg/kg i.v., 0, 4 and 8 h postinjury) improved the rate and extent of functional recovery measured using Basso, Beattie, Bresnahan (BBB) scoring and footprint analysis. The effect of MP treatment on BBB score was apparent the day after SCI whereas the effect of NgR(310)ecto-Fc was not apparent until 2 weeks after SCI. NgR(310)ecto-Fc or MP treatment resulted in increased axonal sprouting and/or regeneration, quantified by counting biotin dextran amine-labeled corticospinal tract axons, and increased the number of axons contacting motor neurons in the ventral horn gray matter caudal to the lesion. Combined treatment with NgR(310)ecto-Fc and MP had a more pronounced effect on recovery of function and axonal growth compared with either treatment alone. The data demonstrate that NgR(310)ecto-Fc and MP act in a temporally and mechanistically distinct manner and suggest that they may have complementary effects.

Analysis of Variance↗

PubMed2004

Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury.

The growth of injured axons in the adult mammalian CNS is limited after injury. Three myelin proteins, Nogo, MAG (myelin-associated glycoprotein), and OMgp (oligodendrocyte myelin glycoprotein), bind to the Nogo-66 receptor (NgR) and inhibit axonal growth in vitro. Transgenic or viral blockade of NgR function allows axonal sprouting in vivo. Here, we administered the soluble function-blocking NgR ectodomain [aa 27-310; NgR(310)ecto] to spinal-injured rats. Purified NgR(310)ecto-Fc protein was delivered intrathecally after midthoracic dorsal over-hemisection. Axonal sprouting of corticospinal and raphespinal fibers in NgR(310)ecto-Fc-treated animals correlates with improved spinal cord electrical conduction and improved locomotion. The ability of soluble NgR(310)ecto to promote axon growth and locomotor recovery demonstrates a therapeutic potential for NgR antagonism in traumatic spinal cord injury.

Animals↗

PubMed2004

Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury.

Axon regeneration after injury to the adult mammalian CNS is limited in part by three inhibitory proteins in CNS myelin: Nogo-A, MAG, and OMgp. All three of these proteins bind to a Nogo-66 receptor (NgR) to inhibit axonal outgrowth in vitro. To explore the necessity of NgR for responses to myelin inhibitors and for restriction of axonal growth in the adult CNS, we generated ngr(-/-) mice. Mice lacking NgR are viable but display hypoactivity and motor impairment. DRG neurons lacking NgR do not bind Nogo-66, and their growth cones are not collapsed by Nogo-66. Recovery of motor function after dorsal hemisection or complete transection of the spinal cord is improved in the ngr(-/-) mice. While corticospinal fibers do not regenerate in mice lacking NgR, regeneration of some raphespinal and rubrospinal fibers does occur. Thus, NgR is partially responsible for limiting the regeneration of certain fiber systems in the adult CNS.

5,7-Dihydroxytryptamine↗