Additional evidence indicates a requirement of APP for neuronal architecture and function also in adult mice. A recent study described reduced dendritic complexity and a moderate reduction in spine density in CA1 neurons of aged (12-15 month old) APP-KO animals [
63], that was associated with pronounced deficits in LTP of aged APP-KO mice [
14,
15,
64], which we had previously shown to be rescued in APPsα-KI mice [
15]. Together, this indicates a dual role of APP for spine structure: an early requirement of APP at stages of spine formation/maturation and also for the maintenance of spines during aging. Further support for a synaptotrophic role of APP and APPsα comes from transgenic mice with moderate overexpression of human WT APP [
65], or indirect up-regulation of APPsα by transgenic expression of the α-secretase ADAM10 [
66], that is enriched at synaptic contacts [
67], which all lead to increased synaptic density. In Tg2576 mice expression of mutant huAPP increased spine density in CA1 and cortical neurons of young mice prior to plaque deposition possibly via APPsα, whereas spine density was decreased in aged animals, presumably due to Aβ-mediated synaptotoxic effects [
16,
17]. In addition, oligomeric forms of Aβ have been reported to compromise synaptic function in Tg2576 mice even before plaque development [
68]. Thus, different APP fragments (e.g. APPsα and Aβ) likely mediate opposing functions for synapse formation or maintenance that are highly relevant not only for normal brain physiology but also AD pathogenesis. As there is a shift towards the amyloidogenic pathway in AD reduced levels of APPsα may contribute to AD pathogenesis [
5]. Indeed, decreased levels of APPsα levels and/or ADAM10 activity (the major the α-secretase) have been reported in the cerebrospinal fluid (CSF) of AD patients [
69‐
74]. Moreover, lowered levels of CSF APPsα are correlated with poor memory performance in aged WT rats [
75]. Intriguingly, a recent study indicated that APPsα can also directly modulate APP processing by reducing BACE activity, and thereby lower Aβ levels in cells and in AD model mice [
76]. Irrespective of whether there is a lack-of-function component in AD pathogenesis caused by diminished APPsα production, the well-established functions of APPsα in neuroprotection (see e. g. [
77] and review by [
1]), synaptic plasticity [
15,
35,
78,
79] and our data from the present study suggest that enhancing/restoring of APPsα levels may be beneficial to counteract and alleviate early AD related symptoms including deficits in spine density.