Jordan Garcia

Introduction. Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects an astonishing percentage of the aging population and causes memory loss and a decline in cognitive function^1,2. It is characterized by abnormal accumulations of amyloid b (Ab) oligomers and neurofibrillary tangles in the cerebral cortex^3,4. Based on ultrastructural analysis, AD brains demonstrate a unique autophagic stress phenotype wherein autophagic vacuoles (AVs) accumulate within large swellings along dystrophic neurites^2,5. This raises an important question as to whether altered autophagic clearance contributes to AD-associated autophagic stress. Previous studies have shown that Ab interferes with axonal transport by interrupting kinesin-mediated anterograde transport⁵. This study focuses on whether retrograde transport is also impaired in AD neurons due to the interaction of Ab oligomers with dynein, the primary motor that drives retrograde transport of late endosomes (LEs) and AVs from distal axons to the soma^5,6. These findings may suggest a potential therapeutic target for preventing or slowing the progression of neurodegeneration in patients with AD. Methods. An AD-related mutant human APP (hAPP) transgenic (Tg) mouse model was utilized. Transmission electron microscopy (TEM) was used to detect the accumulation of AV-like vesicles and the distribution and motility of AVs along the axon of AD neurons cultured from the mutant hAPP Tg mice. Immuno-isolation of LEs/AVs with anti-Rab7-coated magnetic beads was used to determine if there was reduced attachment of dynein intermediate chain (DIC) to the purified LEs/amphisomes in mutant hAPP mouse brains relative to WT littermates. Results. Amphisomes (organelles formed through the fusion of autophagosomes and endosomes) aggregated in distal axons and at the synaptic terminals of mutant hAPP Tg mouse brains^5,7. Retrograde transport of amphisomes was compromised in mutant hAPP Tg neurons, leading to presynaptic and axonal retention of AVs⁵. Cytoplasmic Ab1-42 oligomers interacted with these aggregated amphisomes in the distal axons of AD mice⁵. The Ab1-42-DIC interaction reduced the recruitment of dynein motor to LEs and amphisomes by interfering with dynein-Snapin coupling, consequentially defecting AV transport⁵. Conclusions. This study showed that soluble, cytoplasmic Ab oligomers interfered with the assembly of the DIC-Snapin complex through interaction with dynein DIC, interrupting cytoplasmic dynein motor recruitment to Snapin-related AVs. This implies that dynein-Snapin coupling and consequently, cargo-motor association, is compromised in response to cytoplasmic aggregation of Ab1-42. These new mechanistic insights into AD-linked autophagic pathology may provide a foundation for AD therapeutic strategies based on rescuing retrograde transport of amphisomes.

1. Alzheimer’s Association (2016). 2016 Alzheimer’s disease facts and figures. Alzheimer’s and Dementia, 12(4), 459-509.
2. Tammineni P, Cai Q. Defective retrograde transport impairs autophagic clearance in Alzheimer disease neurons. Autophagy. 2017 Mar 20; 13(5); 982-984.
3. Rubinsztein D, Bento C, Deretic V. Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J Exp Med. 2015 Jun 29; 212(7): 979–990.
4. Menzies F, Fleming A, Rubinsztein D. Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci. 2015 Jun; 16(6): 345–357.
5. Tammineni P, Ye X, Feng T, Aikal D, Cai Q. Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons. Elife. 2017 Jan 13; 6.
6. Cheng XT, Zhou B, Lin MY, Cai Q, Sheng ZH. Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes. The Journal of Cell Biology 2015 May 4; 209(3): 377-386.
7. Sanchez-Wandelmer J, Reggiori F. Amphisomes: out of the autophagosome shadow? The Embo Journal. 2013; 32: 3116-3118.