Expansive Gene Transfer in the Rat CNS Rapidly Produces Amyotrophic Lateral Sclerosis Relevant Sequelae When TDP-43 is Overexpressed

Abstract

Improved spread of transduction in the central nervous system (CNS) was achieved from intravenous administration of adeno-associated virus serotype-9 (AAV9) to neonatal rats. Spinal lower motor neuron transduction efficiency was estimated to be 78% using the highest vector dose tested at a 12-week interval. The widespread expression could aid studying diseases that affect both the spinal cord and brain, such as amyotrophic lateral sclerosis (ALS). The protein most relevant to neuropathology in ALS is transactive response DNA-binding protein 43 (TDP-43). When expressed in rats, human wild-type TDP-43 rapidly produced symptoms germane to ALS including paralysis of the hindlimbs and muscle wasting, and mortality over 4 weeks that did not occur in controls. The hindlimb atrophy and weakness was evidenced by assessments of rotarod, rearing, overall locomotion, muscle mass, and histology. The muscle wasting suggested denervation, but there was only 14% loss of motor neurons in the TDP-43 rats. Tissues were negative for ubiquitinated, cytoplasmic TDP-43 pathology, suggesting that altering TDP-43's nuclear function was sufficient to cause the disease state. Other relevant pathology in the rats included microgliosis and degenerating neuronal perikarya positive for phospho-neurofilament. The expression pattern encompassed the distribution of neuropathology of ALS, and could provide a rapid, relevant screening assay for TDP-43 variants and other disease-related proteins.

NF-κB is involved in brain repair by stem cell factor and granulocyte-colony stimulating factor in chronic stroke

“…Research findings collected from both stroke patients and animal models of stroke have revealed a time-dependent and functional recovery-related shifting of the somatosensorimotor area in both hemispheres. In the early stages (the acute and subacute phases) after stroke, extensive activities appear in the contralesional motor cortex (Dijkhuizen et al, 2001;Tombari et al, 2004), whereas in the recovery stage of stroke (the chronic phase) the somatosensorimotor activities responding to the affected limbs are transferred and reorganized in the ipsilesional cortex near the infarct area (Carmichael, 2012;Sharma and Cohen, 2012;Tombari et al, 2004;Wang et al, 2010a). The greater the involvement of the ipsilesional networks, the better functional recovery is observed (Calautti and Baron, 2003;Carmichael, 2012;Sharma and Cohen, 2012).…”

Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9

“…Subsequent investigation has consistently confirmed that AAV9-IV administration to newborn mice induces efficient neuronal transduction. Wang et al [82] have documented a maximal transduction of 78% spinal lower MNs. The authors also detected significant transgene expression levels in the brain, both in neurons and glia, which according to Miyake et al [37] are stable for at least 18 months.…”

Chronic Psychological Distress as an Inducer of Microglial Activation and Leukocyte Recruitment into the Area Postrema

“…4). The CD45 + /CD11b - immunophenotype with high intensity and round shape was classified as any type of circulating immune cell such as lymphocytes and with low intensity as longitudinal ramified microglia (resting microglia); the CD45 + /CD11b + immunophenotype with high intensity was classified as monocytes, macrophages or reactive microglia/amoeboid (phagocytic) microglia and with low intensity as longitudinal ramified microglia (resting), and the CD45 - /CD11b + immunophenotype as amoeboid (phagocytic) microglia and longitudinal ramified microglia (resting microglia) [4,22,23,24,29]. …”