Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U

Abstract

TDP-43 is a multifunctional DNA/RNA-binding factor that has been implicated in the regulation of neuronal plasticity. TDP-43 has also been identified as the major constituent of the neuronal cytoplasmic inclusions (NCIs) that are characteristic of a range of neurodegenerative diseases, including the frontotemporal lobar degeneration with ubiquitin+ inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). We have generated a FTLD-U mouse model (CaMKII-TDP-43 Tg) in which TDP-43 is transgenically overexpressed in the forebrain resulting in phenotypic characteristics mimicking those of FTLD-U. In particular, the transgenic (Tg) mice exhibit impaired learning/memory, progressive motor dysfunction, and hippocampal atrophy. The cognitive and motor impairments are accompanied by reduced levels of the neuronal regulators phospho–extracellular signal-regulated kinase and phosphorylated cAMP response element-binding protein and increased levels of gliosis in the brains of the Tg mice. Moreover, cells with TDP-43+, ubiquitin+ NCIs and TDP-43–deleted nuclei appear in the Tg mouse brains in an age-dependent manner. Our data provide direct evidence that increased levels of TDP-43 protein in the forebrain is sufficient to lead to the formation of TDP-43+, ubiquitin+ NCIs and neurodegeneration. This FTLD-U mouse model should be valuable for the mechanistic analysis of the role of TDP-43 in the pathogenesis of FTLD-U and for the design of effective therapeutic approaches of the disease.

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

“…Such TDP-43 oligomers exist in the FTLD-TDP patients as proven by our conformational-dependent TDP-43 antibody and confirmed by immunolabelling. Our result on the toxicity of the full-length TDP-43 is consistent with the studies showing that TDP-43 neurotoxicity in Caenorhabditis elegans is independent of caspase-3 cleavages 50 and elevation of TDP-43 expression in the forebrain of mice is sufficient to generate FTLD-TDP-like pathology, in which the TDP-43 generates large insoluble aggregation without much truncated species 25 . At this point, whether the truncated TDP-43 also forms amyloid oligomers and the exact role of such oligomers in the pathogenesis remain unknown.…”

“…6). This line of transgenic mice expressing full-length TDP-43 in the forebrain has been shown to recapitulate FTLD-TDP-like pathology 25 . The TDP-43 Tg mice were deficient in the learning/ memory capabilities and motor functions with age.…”

“…On the other hand, overexpression of the fulllength or N-terminus-truncated TDP-43 in yeast is toxic and forms cytoplasmic aggregates 22 . The rats injected with a viral TDP-43 construct have undergone neuronal apoptosis 23 , and TDP-43 transgenic mice partially recapitulate ALS and FTLD-TDP 24,25 . Despite the emerging biological studies on the pathogenic role of TDP-43, several studies have suggested that RRM1 (refs 26,27), RRM2 (ref.…”

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

“…In addition, although premature sudden death prevented the assessment of cognitive function in previous studies using mutant TDP-43 transgenic animal models, cortical neuron degeneration has been consistently observed. 11,14,19,20,28 Therefore, our findings in hemizygous TDP-43 M337V mice do not necessarily contradict previous findings only reporting motor dysfunction in TDP-43 transgenic mice. Unlike other transgenic animal models showing increased expression of total TDP-43, the hemizygous TDP-43 M337V model does not demonstrate significantly changed expression of total TDP-43 in the brain and spinal cord, 29 indicating very low transgene expression.…”

“…[11][12][13][14][15][16][17][18][19][20] However, either premature death before the presence of full behavior impairments or extremely aggressive disease progression in many of these animal models make the interpretation of behavioral and neuropathological measurements, especially cognitive assessment, difficult. The TDP-43 M337V transgenic (Tg) mouse (i.e., Prnp-TARDBP* M337V; The Jackson Laboratory, stock no.…”