Lysosomal subcellular distribution in neurons: Are there synaptic lysosomes?

BACKGROUND: Despite Alzheimer's disease's first description 114 years ago1 , the mechanisms driving the most common late-onset forms' molecular etiology and neuropathophysiology remain elusive. While considering its elaborate display of pathological hallmarks, recent advances have described synapse loss as the most accurate correlate of disease progression2 . A wide array of data, including insights from human genetics, preclinical AD models, clinical research, and trials, has continuously linked a dysfunctional lysosomal network to pathological aging and disease onset. However, evidence correlating lysosomal dysfunction with early synapse loss is still lacking. Here, we aim to characterize the subcellular distribution of neuronal lysosomes, hypothesizing that these complex organelles localize to both presynaptic and postsynaptic terminals. METHOD: We have analyzed the subcellular distribution of synaptic and non-synaptic associated LAMP-1+ organelles in our established mature primary hippocampal and cortical mouse neuronal in vitro model and adult mouse brain synaptosomes. We applied quantitative single-cell analysis using ICY and ImageJ software for analytical purposes. RESULT: Our results show that the subcellular distribution of (endo)lysosomes is highly compartmentalized and dynamic. Based on the % of (endo)lysosomes in the neuronal soma, we documented that roughly 42% of (endo)lysosomes distribute along dendrites and 37% along the axon initial segment (AIS). Remarkably, we report that close to 8% of the total (endo)lysosomal pool was associated with synapsin, a presynaptic compartment marker. We also reveal that about 26% of (endo)lysosomes colocalized with PSD-95, a postsynaptic compartment marker, constituting 60% of the dendritic (endo)lysosomes. Moreover, we found LAMP-1 enriched in mouse brain synaptosomes against nuclear, non-nuclear, non-synaptosomal and membrane fractions. We are currently pushing to characterize these synaptic (endo)lysosomes' function. CONCLUSION: These results suggest that (endo)lysosomes are present at synapses. In the future we would like to establish whether its dysfunctional activity and trafficking act as a catalyst in the very early stages of synaptic dysfunction in the aging brain, potentially contributing to LOAD etiology and development. References: (1) Alzheimer, A., 1907. Uber einen eigenartigc Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psyciatrie und Psychisch-Gerichtliche Medizin 64, 3. (2) Tampellini, D., Gouras, G., 2010. Synapses, synaptic activity and intraneuronal Aβ in Alzheimer's disease. Front Aging Neurosci. 2, 13. DOI: 10.3389/fnagi.2010.00013.