Intracellular deposition, microtubule destabilization, and transport failure: An early pathogenic cascade leading to synaptic decline

Protein deposition is a common event in age-related neurological diseases that are characterised by neuronal dysfunction and eventual cell death. Here, cultured hippocampal slices were infused with the lysosomal disrupter chloroquine to examine the link between abnormal protein processing/deposition and early synaptopathogenesis. Tau species of' 55 to 69 kDa increased over several days of treatment with chloroquine. while the protein and message levels of synaptic markers were selectively reduced. Neurons of subfields CA1, CA3, and dentate gyrus accumulated protein deposits recognised by antibodies against paired helical filaments and ubiquitin, and this was accompanied by tubulin fragmentation and deacetylation, The deposition filled the basal pole of pyramidal neurons, encompassing the area of the axon hillock and initial dendritie branching but without causing overt neuronal atrophy. Neurons containing the polar aggregates exhibited severely impaired transport along basal dendrites. Transport capability was also lost along apical dendrites, the Opposite direction of deposited material in the basal poled thus. perpetuating the problem beyond physical blockage must he the associated loss of microtuhule integrity. These data indicate that transport failure forms a link between tau deposition and synaptic decline, thus shedding light on how protein aggregation events disrupt synaptic and cognitive functions before the ensuring cellular destruction.