Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and there are no effective options for prevention and treatment. AD pathology is characterized by insoluble amyloid-β (Aβ) accumulation. When amyloid precursor protein (APP) cleavage is shifted from the amyloidogenic pathway to the non-amyloidogenic pathway, it releases the soluble amyloid precursor protein-alpha (sAPPα), promoting a further Aβ reduction. The neuroprotective, neurotrophic, neurogenic, synaptogenic and neuronal plasticity- and memory-enhancing properties of sAPPα mean that it serves as an attractive therapeutic target in the treatment of AD. The C-terminal 16 amino acid peptide (CTα16) is the only difference between sAPPα and sAPPβ, a less active protein fragment that is produced in the amyloidogenic pathway. Previous work from our lab found that CTα16 increased both the induction and persistence of long- term potentiation (LTP) in a concentration- and protein synthesis-dependent manner. Thus, CTα16 may play an essential role in endowing the sAPPα fragment with its enhanced beneficial effects. With its smaller size, CTα16 holds stronger potential in drug design. AAV-PHP.eB is an efficient vector for periphery gene delivery to cross the blood brain barrier (BBB). However, the enhanced CNS tropism is limited to some strains of mice. To overcome this limitation, TAT, a cell-penetrating peptide, may help target proteins pass through the BBB.
The principal aim of my project was to deliver AAV-PHP.eB-HA-HA-sAPPα or AAV- PHP.eB- TAT-HA-HA-CTα16 intravenously to APPswe/PS1dE9 mice to establish a new effective peripheral gene therapy for AD. To understand the functionality of different peptides in vitro, a study was conducted to test the LTP persistence in area CA1 of acute hippocampal slices from 16 to 23-month-old female wild type (WT) or transgenic (Tg) mice, and treated with 1 nM CTα16, HA-HA-CTα16, or TAT-HA-HA-
CTα16 peptides. The results indicated that LTP persistence could be significantly enhanced by all peptides in old WT mice, and the same results were shown in slices from old Tg mice treated with 1 nM TAT-HA-HA-CTα16 peptide. For the main study, female WT or Tg mice were given a single tail vein injection at 6 months of age and after 3 months, brain samples were harvested for electrophysiology and post-mortem analyses. The results showed that both HA-HA-sAPPα and TAT-HA-HA-CTα16 produced a promising therapeutic effect in rescuing LTP in the Tg mice. The post-mortem analyses showed that both treatments also dramatically slowed the amyloid plaque load development, a key neuropathological indicator of AD, in both the hippocampus and cerebral cortex.
The results of this study indicate that the systemic delivery of AAV-PHP.eB-HA-HA- sAPPα or AAV-PHP.eB-TAT-HA-HA-CTα16 for the expression of HA-HA-sAPPα or TAT- HA-HA- CTα16 in brain tissue may serve as a promising non-invasive therapeutic approach for the treatment of AD. This approach effectively mitigated synaptic deficits and amyloid plaque accumulation in an AD mouse model, which may potentially prevent or attenuate AD progression.