Therapeutic potential of secreted APPsalpha for Tau associated synaptic dysfunction and pathology
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Aim 1: Regarding the role of APPsα for Tau induced pathology we demonstrated that P301S mice exhibit an aberrantly increased LTP at 16-18 weeks of age, whereas LTD was unaffected. We showed that acute application of nanomolar amounts of recAPPsα to brain slices restores normal LTP, and basal synaptic transmission indicating a homeostatic function of recAPPsα on a rapid time scale. Further, in vivo expression of APPsα in the hippocampus restored normal spine density of CA1 pyramidal cells even at advanced stages of Tau pathology. Together, these data corroborate therapeutic effects of APPsα for Tau-induced synaptic pathology. As a further key finding we identified a pronounced loss of GABAergic interneurons in the hippocampus of P301S mice as the earliest pathological event that clearly precedes the accumulation of pathological Tau species. Thus, interneuron loss and aberrant LTP may disturb neuronal circuits important for hippocampal function and cognitive behavior. These data obtained in P301S mice are further strengthened by similar findings in THY-Tau22 mice. Also in THY-Tau22 mice AAV-APPsα rescued spine density deficits of CA1 neurons. In summary, these data further corroborate that APPsα is of therapeutic relevance for Tauinduced synaptic pathology both in a preventive setting (P301S model), but also when applied in the presence of established pathology (THY-Tau22). Aim2: Regarding the effects of APPsα in comparison to APPsβ we demonstrated distinct in vivo roles of APPsα versus APPsβ in the regulation of spine density, synaptic plasticity and cognition. APPsα efficiently rescued deficits in spine density, synaptic plasticity and spatial reference memory in mice lacking both APP and APLP2. In contrast, APPsb failed to show any detectable effects on synaptic plasticity and spine density. The C-terminal 16 amino acids of APPsα (lacking in APPsb) proved sufficient to facilitate LTP in a mechanism that depends on nicotinic a7-nAChRs. Further, APPsa showed high-affinity, allosteric potentiation of heterologously expressed a7-nAChRs in oocytes. Collectively, we identified a7-nAChRs as a crucial physiological receptor specific for APPsα and show distinct in vivo roles for APPsα versus APPsβ. Together, both aims were successfully addressed and lend further support to the concept of harnessing the therapeutic potential of APPsα and CTα16 for AD and possibly other diseases in which neurons a damaged.
Publications
- (2018) Distinct in vivo roles of secreted APP ectodomain variants APPsalpha and APPsbeta in regulation of spine density, synaptic plasticity, and cognition. EMBO J 37
Richter MC, Ludewig S, Winschel A, Abel T, Bold C, Salzburger LR, Klein S, Han K, Weyer SW, Fritz AK, Laube B, Wolfer DP, Buchholz CJ, Korte M, Muller UC
(See online at https://doi.org/10.15252/embj.201798335) - (2021) APPsalpha rescues impaired Ca(2+) homeostasis in APP- and APLP2-deficient hippocampal neurons. Proc Natl Acad Sci U S A 118
Ludewig S, Herrmann U, Michaelsen-Preusse K, Metzdorf K, Just J, Bold C, Muller UC, Korte M
(See online at https://doi.org/10.1073/pnas.2011506118)
