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The microtubule-dynamin binding inhibitor peptide PHDP5 rescues spatial learning and memory deficits in Alzheimer's
Chia-Jung Chang1, Zacharie Taoufiq1, Hiroshi Yamada2
1Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan.
Abstract:
Dynamin is a microtubule (MT) binding protein playing a key role in vesicle endocytosis. In a brain slice model, tau loaded in presynaptic terminals assembles MTs, thereby impairing vesicle endocytosis via depletion of cytosolic dynamin. The peptide PHDP5, derived from the pleckstrin homology domain of dynamin 1, inhibits dynamin-MT interaction and rescues endocytosis and synaptic transmission impaired by tau when co-loaded in presynaptic terminals. We tested whether in vivo administration of PHDP5 could rescue the learning/memory deficits observed in Alzheimer's disease (AD) model mice. A modified PHDP5 incorporating a cell-penetrating peptide (CPP) and a FITC fluorescent marker was delivered intranasally to Tau609 transgenic (Tg) and 3xTg-AD mice. FITC-positive puncta were observed in the hippocampus of mice infused with PHDP5 or scrambled (SPHDP5) peptide, but not in saline-infused controls. In the Morris water maze (MWM) test for spatial learning/memory, AD model mice treated with FITC-PHDP5-CPP showed prominent improvements in learning and memory, performing close to the level of saline-infused WT mice control. In contrast, mice treated with a scrambled construct (FITC-SPHDP5-CPP) showed no significant improvement. We conclude that PHDP5 can be a candidate for human AD therapy.
Insights
The peptide PHDP5, derived from dynamin 1, improved learning and memory in Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Dynamin is crucial for vesicle endocytosis, interacting with microtubules (MTs).
- Tau protein in Alzheimer's disease (AD) disrupts endocytosis by promoting MT assembly, depleting dynamin.
- The peptide PHDP5 inhibits dynamin-MT interactions, rescuing endocytosis in vitro.
Purpose of the Study:
- To investigate if intranasal administration of PHDP5 can ameliorate learning and memory deficits in AD model mice.
- To assess the therapeutic potential of PHDP5 for Alzheimer's disease.
Main Methods:
- A modified PHDP5 peptide (FITC-PHDP5-CPP) was delivered intranasally to Tau609 transgenic and 3xTg-AD mice.
- Localization of the peptide in the hippocampus was confirmed using fluorescence microscopy.
- Spatial learning and memory were evaluated using the Morris water maze (MWM) test.
Main Results:
- FITC-positive puncta were detected in the hippocampus of mice treated with FITC-PHDP5-CPP and a scrambled control (FITC-SPHDP5-CPP).
- AD model mice treated with FITC-PHDP5-CPP demonstrated significant improvements in MWM performance, nearing wild-type levels.
- Treatment with the scrambled peptide showed no significant cognitive benefits.
Conclusions:
- Intranasal administration of PHDP5 effectively rescues learning and memory deficits in mouse models of Alzheimer's disease.
- PHDP5 demonstrates potential as a therapeutic candidate for human AD treatment.
