UC Irvine

Accumulation of Aβ and chronic inflammation are hallmark neuropathological findings that define Alzheimer’s Disease. Both Aβ and pro-inflammatory cytokines have been linked to poor cognitive function, likely owing to impaired neuronal signaling and attenuation of neurotrophic factor signaling. BDNF endosomal transport is a key signaling system facilitating many aspects of healthy brain function and synaptic plasticity. Furthermore, proper intracellular transport via the endosomal trafficking system is crucial to maintain steady-state BDNF signaling. This dissertation focuses on how Aβ and IL-1β act both synergistically and distinctly to induce a state of abnormal neuronal endosome transport of BDNF. Utilizing a specialized microfluidic isolation chamber for in vitro primary neuronal cultures, we demonstrate that Aβ oligomers compromise BDNF retrograde transport by impairing endosomal transport rate, resulting in impaired downstream signaling driven by BDNF. In a similar fashion, we show that IL-1β also attenuates BDNF endosomal trafficking flux and the dispersion of BDNF signaling endosomes throughout neurite networks in cultures. Distinct from Aβ however, the mechanism for IL-1β-induced deficits to BDNF endosomal signaling did not arise from impaired rate of transport of the BDNF-TrkB receptor complex. Rather, IL-1β may be associated with a Ub-dependent presynaptic sorting deficit. Our data suggests that ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that functions to regulate cellular ubiquitin, mediates these trafficking deficits, since the irregularity in BDNF trafficking can be reversed by increasing cellular UCH-L1 levels. UCH-L1 is important for regulating neurotrophin receptor sorting and supporting retrograde transport. Thus, this work supports the idea that in AD or other neurological conditions where chronic inflammation is present, down-regulated UCH-L1 may drive BDNF trafficking deficits, compromising synaptic plasticity and neuronal survival. Collectively, the data indicate that both Aβ and IL-1β distinctly contribute to BDNF trafficking deficits, and that Aβ-induced deficits can be rescued in vitro by UCH-L1 overexpression.