Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer’s disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function—nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity—appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals.

Loss of mitochondrial homeostasis are evident in Alzheimer's disease (AD)1. However, the underlying mechanisms remain largely elusive. In this study, we report that lncMtDloop, an age-related and conserved long noncoding RNA derived from mitochondrial DNA (mtDNA) D-loop, is crucial for sustaining mitochondrial transcription and homeostasis, and associates with Alzheimer’s pathogenesis. Notably, the level of lncMtDloop expression is diminished in the brains of human AD patients and the 3xTg mouse model, whereas the failure to recruit mitochondrial transcription factor A (TFAM) leads to the deregulated mitochondrial transcription. Restoring lncMtDloop expression not only significantly improves mitochondrial transcription, morphology and function, but also enhances mitophagy, ameliorates AD-like pathology, which these subcellular effects extend to a dramatic reversal of deficits in synaptic and cognitive behaviors of the 3xTg mouse model. Collectively, our findings show the decreased lncMtDloop expression potentiates AD risk, thereby revealing an unexpected mitochondrial mechanism contributing to AD pathogenesis and opens a new door for therapeutic intervention.

PTPRT (receptor-type tyrosine-protein phosphatase T), as a brain-specific type 1 transmembrane protein, plays an important function in neurodevelopment and synapse formation. Here, we identified that PTPRT is a novel substrate of ADAM10- and presenilin 1/γ-secretase. The intracellular domain (PICD), which was released from the cleavage of PTPRT, translocated to the nucleus and dephosphorylated signal transducer and activator of transcription 3 (pSTAT3Y705). Overexpression of the PICD alone profoundly altered gene expression in neuronal cells. We further found that the downregulation of Ptprt expression was negatively correlated to the accumulation of pSTAT3Y705 in the brains of human Alzheimer’s disease (AD) and model mice. PICD alone not only decreased pSTAT3Y705 and Aβ deposition but also markedly improved synaptic function and behavioral deficits in APP/PS1 mice. Our data demonstrate a distinct role of the ADAM 10- and presenilin 1/γ-secretase-dependent cleavage of PTPRT in mitigating neurodegeneration of Alzheimer’s disease.