Figure 5.

Overview of contributing factors in AD and potential intervention strategies. Shown are only the most important factors, which are also described in more detail in this article's main text. In the upper left corner, we see the neurovascular system. Both characteristics of blood vessels (e.g., atherosclerosis and endothelial dysfunction) (Love and Miners, 2016), as well as aspects of the blood-brain barrier (Sweeney et al., 2018), play a role in AD. A particular aspect here is the role of neural immunity, both with the brain-own microglia cells and the effect of systemic immune cells, e.g., mediated by antibodies (Heneka et al., 2015a,c). On the upper right corner, we see an illustration of the multiscale network structure of the brain. Stimulation approaches as deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) act on the larger scale of a network-level; nevertheless, the actual changes happen on the level of synapses. Also, transmitter interventions develop their effects mainly at the micro-scale of synapses. In the lower right corner, basic molecular pathways in the extra- and intracellular space of a neuron are shown. We focused here on the processing of the two hallmark proteins Abeta and Tau, as well as the Notch-1 pathway, which is involved in memory (Marathe and Alberi, 2015) and plasticity (Brai et al., 2015). We illustrate the APP procession by the amyloidogenic or non-amyloidogenic way and its interaction with Notch-1 processing and, second, in the axon, the hyperphosphorylation and aggregation of Tau. A more detailed description of the named treatment strategies presently under development is provided in Table 1. NGF, nerve growth factor; Abeta, amyloid-beta; p-tau, phosphorylized Tau protein; APP, amyloid precursor protein; APPα, APP in alpha-helix configuration; NECD, Notch extracellular domain; NICD, Notch intracellular domain.