gms | German Medical Science

Introduction & objectives: Loss of synaptic function is the immediate cause of cognitive decline and memory dysfunction in Alzheimer’s disease. In previous studies we found substantial structural and functional alterations at excitatory postsynapses in the immediate vicinity of fibrillar amyloid beta plaques, such as loss of dendritic spines. In the present study we aim to characterize alterations in the presynaptic compartment of excitatory synapses.

Materials & methods: To this end, we crossed mice expressing the endogenous vesicular glutamate transporter (vGlut) tagged with the fluorophore venus, a photostable derivative of yellow fluorescent protein, with PS1/APP mice expressing mutant presenilin 1 (PS1) and amyloid precursor protein (APP) as a model of hereditary Alzheimer’s disease. After implantation of a cranial window, we performed repeated in vivo multiphoton imaging of the superficial cortical layers to assess alterations in venus-tagged presynaptic glutamatergic terminals.

Results: In the ficinity of fibrillar plaques, we found pronounced alterations, such as a reduction in the number of presynaptic terminals as well as numerous dystrophic axons, appearing as swollen structures, filled with fluorophore. Lastly, we found altered vesicle dynamics by performing in vivo fluorescence recovery after photobleaching (FRAP) experiments.

Conclusions: Together these results demonstrate that synaptic alterations in the vicinity of fibrillar amyloid beta plaques affect both the pre- as well as the postsynaptic side. Future experiments may help us to understand the temporal and causal relationship between pre- and postsynaptic pathology.