Biology subjects

Dhandapani, R.

Publications and source records attributed to Dhandapani, R..

3 recordsLinked to original sources

bioRxiv2021

Sustained TREM2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer s disease

TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimers disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. We generated a transgenic mouse model of reduced TREM2 shedding (Trem2-IPD) through amino acid substitution of ADAM-protease recognition site. We found that Trem2-IPD mice displayed increased TREM2 cell surface receptor load, survival and function in myeloid cells. Using single cell transcriptomic profiling of mouse cortex we show that sustained TREM2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to A{beta} pathology in a mouse model of Alzheimers disease. Our data indicate that reduction of TREM2 proteolytic cleavage aggravates neuroinflammation during the course of AD pathology suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.

neuroscience↗

bioRxiv2017

Control of mechanical pain hypersensitivity through ligand-targeted photoablation of TrkB positive sensory neurons

SummaryMechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both necessary and sufficient for producing pain from light touch after nerve injury. Mice in which TrkB-Cre expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.\n\nHighlightsO_LITrkB+ neurons detect light touch under basal conditions\nC_LIO_LITrkB+ neurons convey mechanical allodynia in neuropathic pain states\nC_LIO_LIA photosensitizing derivative of BDNF allows for photoablation of TrkB+ neurons\nC_LIO_LIBDNF-guided photoablation reverses allodynia in multiple types of neuropathic pain\nC_LI

neuroscience↗

bioRxiv2017

Molecule guided laser ablation as a novel therapeutic strategy to control itch.

Itch is a major symptom of many chronic skin diseases that can exacerbate inflammation by provoking excessive scratching and causing skin damage. Here we develop a novel technology to control itch through molecular guided delivery of a phototoxic agent and near infrared (IR) illumination of the skin. Exploiting the selective binding of the pruritogen Interleukin-31 to itch sensing cells, we generate an engineered IL31SNAP ligand derivative (IL31K138A-SNAP) that binds to cells but does not evoke signaling or provoke scratching when injected in vivo. Conjugation of IL31K138A-SNAP to the photosensitizer IRDye(R)700DX phthalocyanine (IR700) and injection of the skin results in long-term reversal of scratching behavior evoked by IL31 upon near IR illumination. We further develop a topical preparation of IL31 K138A-SNAP-IR700 that strikingly, reverses behavioral and dermatological indicators in mouse models of Atopic Dermatitis (AD) and the genetic skin disease Familial Primary Localized Cutaneous Amyloidosis (FPLCA). We demonstrate that this therapeutic effect results from selective retraction of itch sensing neurons in the skin, breaking the cycle of itch and disruption of the skins barrier function. Thus, molecule guided photoablation is a powerful new technology for controlling itch and treating inflammatory skin diseases.

neuroscience↗