Effects Of The γ-secretase Inhibitor DAPT On Hippocampal Synaptic Transmission And Activity-dependent Synaptic Plasticity

Alzheimer’s disease, a progressive neurodegenerative disorder and a most common dementia, is characterized by the presence of extracellular plaques, intracellular neurofibrillary tangles, inflammation, neuron loss and synapse loss in the brains of Alzheimer’s sufferers. Amyloid beta (Aβ) plaque peptides, including Aβ1-42, are produced as a result of the sequential proteolytic cleavages of a protein precursor, involving β- and γ-secretase enzymes. Compounds that inhibit or modulate y-secretase, a pivotal enzyme which generates beta-amyloid, are potential therapeutic drugs for Alzheimer’s disease (AD). However, γ-secretase inhibitors might cause inevitable toxicity in humans because of functional effects of the drug. Therefore, the prevention and treatment of Alzheimer disease may require a more detailed understanding of how cognitions are affected in the disease process. It is well known that hippocampus plays important roles in learning and memory. Long term potentiation (LTP) is widely thought to be the underlying mechanism of synaptic plasticity and memory formation. Together, for a better understanding of the relationships between y-secretase and memory, a set of studies was implemented in area CA1 of hippocampal slices from wild Wistar rats, using extracellular recording methods. The compound, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of gamma-secretase, is able to reduce amyloid beta production and to inhibit Notch activities as well. After DAPT application on the acute hippocampal slices, hippocampal synaptic transmission and activity-dependent synaptic plasticity were affected, which might be associated with lower amyloid beta formation or impaired Notch processing resulting from inhibition of y-secretase. y-Secretase inhibitors were diluted from DMSO stock solutions to yield final concentrations in ACSF with 0.05% DMSO. Our results showed that DAPT treatment impaired late-phase, but not early-phase long-term potentiation without change in basal synaptic transmission of Schaffer collateral SC-CA1 synapses. LTP’s long-term persistence and maintenance were significantly impaired with DAPT application, whereas LTP induction was not affected.In summary, we investigate the acute effects of DAPT on rat’s hippocampal synaptic transmission and plasticity by using acute bath application of DAPT. The characterization of DAPT would contribute to the development of better γ-secretase targeted therapeutics against Alzheimer disease with lower side effects.In conclusion, the data suggests that y-secretase plays an important role in hippocampal activity-dependent synaptic plasticity which might be associated with Aβ or Notch signaling pathways. Besides, the physiological role of y-secretase in activity dependent synaptic plasticity, the pharmaceutical targeting of y-secretase to battle Alzheimer’s disease might itself cause a decline of memory formation.