Abbreviated Title: NSC-Mediated Synaptic Resistance To Ab Oligomers
ABSTRACT
Background Adult hippocampal neurogenesis plays an important role in supporting synaptic plasticity and cogntive function. We have recently reported that the presence of higher numbers of neural stem cells (NSC) in the hippocampus of non-demented individuals who display neuropathology consistent with a fully symptomatic stage of Alzheimer’s disease (AD), is associated with a unique synaptic proteome and decreased synaptic sensitivity to the disruptive binding of the toxic amyloid beta oligomers (Abo), an event linked to onset of dementia in AD. While these findings suggest a link between NSC and synaptic resistance to Ab, the involved mechanism remains to be determined. With this goal in mind, in the present work we investigated the ability of exosomes secreted from hippocampal NSC to promote synaptic resilience to Abo.
Methods Exosomes, isolated from conditioned media collected from hippocampus NSC (NSC-exo) or mature hippocampal neuronal cultures (MN-exo), were delivered by intracerebroventricular (icv) injection into adult wild type mice 4 to 24 hours before assessment of Abo-induced suppression of hippocampal long-term potentiation (LTP) and memory deficits. Ab oligomers binding to synapses was assessed in cultured hippocampal neurons and on synaptosomes isolated from hippocampal slices prepared from wild type mice and from an inducible mouse model of NSC ablation (Nestin-δ-HSV-TK mice) treated with exosomes for 4-24 hours before Abo treatment.
Results We found that icv administration of NSC-exo, but not by MN-exo, abolished Abo-induced suppression of hippocampal LTP and subsequent memory deficits. We further found that in hippocampal slices and cultured neurons, NSC-exo significantly decreased Abo binding to the synapse. Similarly, ablation of endogenous NSC in Nestin-δ-HSV-TK mice increased synaptic Abo binding, which was reversed by exogenous NSC-exo, but not by MN-exo.
Conclusions These results identify a novel mechanism linking NSC-exo and synaptic susceptibility to the dysfunctional impact of Abo that may underscore the ability of certain individuals with increased neurogenesis to resist the cognitive decline normally associated with AD neuropathology and unmask a novel target for the development of a new treatment concept for AD centered on promoting synaptic resilience to toxic amyloid proteins.
Maria-Adelaide Micci, Balaji Krishnan, Elizabeth Bishop, Wen-Ru Zhang, Jutatip Guptarak, Auston Grant, Arjun Luthra, Olga Zolochevska, Steven G. Kernie, Giulio Taglialatela
Mol Neurodegeneration 14, 25 (2019)
