TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies.protein aggregation | neuronal apoptosis T DP-43 is a 43-kDa, ubiquitously expressed protein, well conserved among eukaryotes (1). This DNA/RNA-binding factor is predominantly located in the nucleus as a dimer (2), and it has been implicated in multiple cellular functions, e.g., transcriptional repression, splicing, and translation (3-6). TDP-43 has also been identified as the pathological signature protein of a range of neurodegenerative diseases (7). The pathological samples of these diseases, which have been termed TDP-43 proteinopathies, are characterized by cytoplasmic and, to a much lesser extent, nuclear TDP-43-positive (+) and ubiquitinated inclusions (UBIs) containing full-length TDP-43, polyubiquinated TDP-43, phosphorylated TDP-43, as well as 35-and 25-kDa carboxy1 fragments of TDP-43 (for reviews, see refs. 7-11). Of the two major categories of TDP-43 proteinopathies are frontotemporal lobar degeneration with ubiquitin (+) inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). It has been estimated that ∼50% of FTLD-U and 80-90% of ALS, which has an incidence rate between 1.5 and 2.5 per 100,000 (12), are signified...