Hyung Jin Ahn, PhD
Assistant Professor
Pharmacology, Physiology and Neuroscience
BHI Core Faculty

Fri, Nov 20 (2.25 PM – 2.45 PM)

Fibrinogen as a Key Player for Cerebral Amyloid Angiopathy-Associated Vascular Pathology
Cerebral amyloid angiopathy (CAA), where Aβ deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in AD patient. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. Hereditary cerebral amyloid angiopathy (HCAA) is a rare familial form of CAA where mutations within the gene for the β-amyloid precursor protein (APP) causes an increase in vascular deposits of Aβ. Since the interaction between Aβ and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, we investigated the role of the Aβ -fibrinogen interaction in HCAA pathology. We showed that the most common forms of HCAA-linked mutations, Dutch (E22Q) and Iowa (D23N), resulted in up to a 50-fold stronger binding affinity of Aβ for fibrinogen. In addition, the stronger interaction between fibrinogen and mutant Aβ s led to a dramatic perturbation of clot structure and delayed fibrinolysis. Immunofluorescence analysis of the occipital cortex showed an increase of fibrin(ogen)/ Aβ co-deposition as well as fibrin deposits in HCAA patients compared to early-onset AD patients and non-demented individuals. Our results suggest the HCAA-type Dutch and Iowa mutations increase the interaction between fibrinogen and Aβ and may lead to cerebrovascular pathologies observed in HCAA.

Max Tischfield, PhD
Assistant Professor of Cell Biology and Neuroscience
SAS, Rutgers-New Brunswick and CHINJ

Fri, Nov 20 (2.50 PM – 3.10 PM)

Brain Drain: Development of meningeal lymphatic networks and the glymphatic system in craniofacial disorders
Skull malformations are associated with cerebrovascular abnormalities that can cause serious complications for fluid balance in the CNS and brain health and function. We discovered that humans with abnormal skull development and inactivating mutations in the transcription factor TWIST1 also have dural cerebral vein malformations. Twist1 and Bmp2/Bmp4 conditional knock-out mouse models revealed that cerebral vein growth and remodeling is tightly coupled with skull development and dependent upon Bone Morphogenetic Protein (BMP) produced from surrounding bone and dura. Twist1 and BMP signaling is also necessary to integrate the development of dural lymphatic vessels (DLVs) with the skull, meninges, and cerebral blood vessels. These findings have clinical significance because DLVs are master regulators for tissue fluid homeostasis in the CNS and, as part of the brain’s glymphatic system, are required for the drainage of macromolecules and waste from CSF. Furthermore, DLVs form a gateway between the CNS and peripheral immune system by facilitating the transport of brain-derived antigens and immune cells to the cervical lymph nodes. As such, their compromise may be associated with neuroimmune dysfunction, neurodegeneration, and cognitive impairments, underscoring the importance of addressing how DLV malformations arise and affect these processes. Thus, we aim to leverage our unique animal models to identify tissue-specific cellular interactions and signaling pathways that integrate the growth and function of DLVs with that of the surrounding environment in normal health and pathologic states.

Stella Elkabes, PhD
Director, Reynolds Family Spine Laboratory
Professor of Neurosurgery

Fri, Nov 20 (3.15 PM – 3.35 PM)

Modulation of Immune and Non-Immune Functions of Astrocytes following Spinal Cord Injury: Role of Toll-Like Receptor 9
The central nervous system (CNS) was historically considered an immune-privileged organ.  However, this concept has changed as convincing evidence demonstrates that CNS infections and injuries as well as neurodegenerative diseases trigger innate immune responses in the brain and spinal cord (SC). Astrocytes and microglia are the principal intrinsic cell types that mount an innate immune response in CNS pathologies. This response is initiated by danger signals that activate pattern recognition receptors (PRRs).  Toll-like receptors (TLRs) are the best-characterized family of PRRs, and are expressed in glia and neurons. Endogenous self-ligands released by stressed and damaged cells activate TLR signaling following CNS injury. This leads to release of inflammatory mediators and induction of sterile neuroinflammation.

Investigations in our laboratory focus on the role of TLRs in traumatic spinal cord injury (SCI) with particular emphasis on TLR9.  Previous studies indicated that intrathecal administration of a TLR9 agonist to mice sustaining a mid-thoracic SC contusion injury exacerbates the pro-inflammatory response and the functional outcomes of SCI.  In contrast, intrathecal delivery of a TLR9 antagonist alleviates SCI-elicited neuropathic pain, bladder dysfunction and neuroinflammation.  Studies to unravel the potential cellular and molecular mechanisms underlying these beneficial effects indicated that treatment with the TLR9 antagonist modifies the glial scar that forms around the lesion core. The antagonist attenuated astrocyte proliferation and increased the percentage of alternatively activated, neuroprotective M2 macrophages at the glial scar. Moreover, there was a reduction in the levels of chondroitin sulfate proteoglycans (CSPGs), inhibitors of axonal re-growth which are predominantly released by reactive astrocytes.  These changes were paralleled by improved preservation of injured proximal axons.  In vitro investigations indicated that direct antagonism of astroglial TLR9 hinders astrocyte proliferation by inhibiting the ERK/MAPK signaling pathway. Moreover, in astrocyte-macrophage co-cultures, the TLR9 antagonist enhanced the chemotaxis of macrophages and their polarization into the M2 phenotype through modulation of astrocyte-to-macrophage signals.  Collectively, these findings suggest that treatment with the TLR9 antagonist creates a favorable milieu at the lesion site.  This could be partly mediated by alterations in astrocyte function and in astrocyte-macrophage interactions.