With Alzheimer's disease (AD) exhibiting reduced ability of neural stem cell renewal, we hypothesized that de novo mutations controlling embryonic development, in the form of brain somatic mutations instigate the disease. A leading gene presenting heterozygous dominant de novo autism-intellectual disabilities (ID) causing mutations is activity-dependent neuroprotective protein (ADNP), with intact ADNP protecting against AD-tauopathy. We discovered a genomic autism ADNP mutation (c.2188C>T) in postmortem AD olfactory bulbs and hippocampi. RNA-Seq of olfactory bulbs also identified a novel ADNP hotspot mutation, c.2187_2188insA. Altogether, 665 mutations in 596 genes with 441 mutations in AD patients (389 genes, 38% AD-exclusive mutations) and 104 genes presenting disease-causing mutations (OMIM) were discovered. OMIM AD mutated genes converged on cytoskeletal mechanisms, autism and ID causing mutations (about 40% each). The number and average frequencies of AD-related mutations per subject were higher in AD subjects compared to controls. RNA-seq datamining (hippocampus, dorsolateral prefrontal cortex, fusiform gyrus and superior frontal gyrus-583 subjects) yielded similar results. Overlapping all tested brain areas identified unique and shared mutations, with ADNP singled out as a gene associated with autism/ID/AD and presenting several unique aging/AD mutations. The large fusiform gyrus library (117 subjects) with high sequencing coverage correlated the c.2187_2188insA ADNP mutation frequency to Braak stage (tauopathy) and showed more ADNP mutations in AD specimens. In cell cultures, the ADNP-derived snippet NAP inhibited mutated-ADNP-microtubule (MT) toxicity and enhanced Tau-MT association. We propose a paradigm-shifting concept in the perception of AD whereby accumulating mosaic somatic mutations promote brain pathology.

• MeSH
• Alzheimerova nemoc * genetika   MeSH
• autistická porucha * genetika   MeSH
• homeodoménové proteiny genetika   MeSH
• lidé MeSH
• mentální retardace * MeSH
• mozek metabolismus   MeSH
• mutace MeSH
• proteiny nervové tkáně genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/-) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet drug candidate NAP (NAPVSIPQ, also known as CP201), which binds to microtubule end-binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane-tagged, GFP-expressing Adnp+/- mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal). In conclusion, we have connected ADNP-related synaptic pathology to developmental and behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave a path toward the clinical development of NAP (CP201) for the treatment of ADNP syndrome.

• MeSH
• aminokyselinové motivy MeSH
• autistická porucha genetika   metabolismus   patologie   patofyziologie   MeSH
• biologické markery metabolismus   MeSH
• buněčná membrána genetika   metabolismus   patologie   MeSH
• chování zvířat MeSH
• dendritické trny metabolismus   patologie   MeSH
• homeodoménové proteiny MeSH
• lidé MeSH
• mikrotubuly genetika   metabolismus   patologie   MeSH
• modely neurologické * MeSH
• mutace MeSH
• myši knockoutované MeSH
• myši MeSH
• naftochinony farmakologie   MeSH
• proteiny nervové tkáně nedostatek   MeSH
• regulace genové exprese MeSH
• synapse metabolismus   patologie   MeSH
• syndrom MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• audiovizuální média MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH