| First Author | Bold CS | Year | 2022 |
| Journal | J Neurosci | Volume | 42 |
| Issue | 29 | Pages | 5782-5802 |
| PubMed ID | 35667850 | Mgi Jnum | J:353536 |
| Mgi Id | MGI:7706259 | Doi | 10.1523/JNEUROSCI.2200-21.2022 |
| Citation | Bold CS, et al. (2022) APPsalpha Rescues Tau-Induced Synaptic Pathology. J Neurosci 42(29):5782-5802 |
| abstractText | Alzheimer's disease (AD) is histopathologically characterized by Abeta plaques and the accumulation of hyperphosphorylated Tau species, the latter also constituting key hallmarks of primary tauopathies. Whereas Abeta is produced by amyloidogenic APP processing, APP processing along the competing nonamyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsalpha. Recently, we demonstrated that APPsalpha has therapeutic effects in transgenic AD model mice and rescues Abeta-dependent impairments. Here, we examined the potential of APPsalpha to mitigate Tau-induced synaptic deficits in P301S mice (both sexes), a widely used mouse model of tauopathy. Analysis of synaptic plasticity revealed an aberrantly increased LTP in P301S mice that could be normalized by acute application of nanomolar amounts of APPsalpha to hippocampal slices, indicating a homeostatic function of APPsalpha on a rapid time scale. Further, AAV-mediated in vivo expression of APPsalpha restored normal spine density of CA1 neurons even at stages of advanced Tau pathology not only in P301S mice, but also in independent THY-Tau22 mice. Strikingly, when searching for the mechanism underlying aberrantly increased LTP in P301S mice, we identified an early and progressive loss of major GABAergic interneuron subtypes in the hippocampus of P301S mice, which may lead to reduced GABAergic inhibition of principal cells. Interneuron loss was paralleled by deficits in nest building, an innate behavior highly sensitive to hippocampal impairments. Together, our findings indicate that APPsalpha has therapeutic potential for Tau-mediated synaptic dysfunction and suggest that loss of interneurons leads to disturbed neuronal circuits that compromise synaptic plasticity as well as behavior.SIGNIFICANCE STATEMENT Our findings indicate, for the first time, that APPsalpha has the potential to rescue Tau-induced spine loss and abnormal synaptic plasticity. Thus, APPsalpha might have therapeutic potential not only because of its synaptotrophic functions, but also its homeostatic capacity for neuronal network activity. Hence, APPsalpha is one of the few molecules which has proven therapeutic effects in mice, both for Abeta- and Tau-dependent synaptic impairments and might therefore have therapeutic potential for patients suffering from AD or primary tauopathies. Furthermore, we found in P301S mice a pronounced reduction of inhibitory interneurons as the earliest pathologic event preceding the accumulation of hyperphosphorylated Tau species. This loss of interneurons most likely disturbs neuronal circuits that are important for synaptic plasticity and behavior. |
