Gene therapy in mice with Alzheimer’s disease preserves memory and learning
Researchers led by a team from the University of California San Diego School of Medicine (UCSD) used gene therapy to prevent learning and memory loss in a mouse model of Alzheimer’s disease (AD ). The results of their experiments, which involved delivering a gene called SynCav1 to the brains of mice, could represent a key step towards testing the approach in humans with neurodegenerative disorder.
Communicate their results in Molecular Therapy-Methods and Clinical Development, the researchers, led by Brian P. Head, PhD, assistant professor in the department of anesthesiology at UCSD School of Medicine and health researcher at the VA San Diego Healthcare System, said: “Our data indicates that SynCav1 gene therapy may be an option for AD and potentially in other forms of neurodegeneration of unknown etiology. Their article is titled “Synapsin-caveolin-1 gene therapy preserves neuronal and synaptic morphology and prevents neurodegeneration in mouse model of AD. “
AD is the most common form of neurodegeneration and cognitive dysfunction in the elderly, the authors wrote. The disorder is characterized by the accumulation of clumps of misfolded proteins called amyloid plaques and tau neurofibrillary tangles, which alter cell signaling and promote neuronal death.
Current AD treatments targeting plaques and tangles only treat symptoms, which the authors say suggests that removing toxic amyloid species on its own may not be enough to reverse functional deficits in the brain. They suggest that reversing and curing AD will likely require a combination of interventional approaches that both decrease toxin aggregation and promote neuronal and synaptic plasticity. “Gene therapies that target neuroprotection and resilience may be an effective option for treating people with AD or other forms of neurodegeneration of different or unknown ethology.”
For their reported studies, the team used an adeno-associated viral (AAv) vector to introduce synapsin-caveolin-1 (AAV-SynCav1) cDNA into the hippocampal region of three-year-old PSAPP AD transgenic mice. month.
PSAPP mice exhibit learning and memory deficits at 9 and 11 months, respectively. These deficits are associated with a decrease in the expression of caveolin-1, a scaffold protein that builds membranes that house cell signaling tools, such as neurotrophin receptors (NTRs) that receive critical extracellular signals, which govern all life and cellular function. With the breakdown and destruction of these membranes, cell dysfunction and neurodegeneration ensue. Previous research has found a decrease in Cav-1 in AD Enron and other conditions. “Preclinical and clinical results revealed that signaling complexes associated with Cav-1 and Cav-1 (NTR and neurotransmitter receptors) were decreased in neurons degenerated in AD, chronic traumatic encephalopathy (CTE) and sclerosis. amyotrophic lateral (ALS) “, the authors wrote.
The researchers administered a single injection of AAV-SynCav1 to the hippocampus of PSAPP mice. The hippocampus is a complex region located deep in the brain that plays a major role in learning and memory. In AD, the hippocampus is one of the first areas of the brain to be damaged. “Our goal was to test whether SynCav1 gene therapy in these AD mouse models could preserve neuronal and synaptic plasticity in targeted parts of the membrane and improve upper brain function,” noted Head.
The results confirmed that at 9 and 11 months, learning and hippocampal memory in mice were preserved. In addition, the researchers found that critical membrane structures and associated neurotrophin receptors also remained intact in animals that received gene therapy. The neuroprotective effects of administration of the SynCav1 gene occurred independently of the reduction in amyloid plaque deposition. “These results are the first to demonstrate that a single hippocampal administration of AAV-SynCav1 to PSAPP mice preserved hippocampal learning at 9 months and memory at 11 months,” the investigators said.
The team had previously demonstrated the neuroprotective properties of SynCav1 in various in vitro and in vivo models, including ischemia, aging, traumatic injury, and in neurodegenerative mice that model a familial form of ALS, “… suggesting that Cav -1 can serve as a central neuroprotective target in a variety of neurodegenerative conditions They say their recently published study now extends the therapeutic potential of SynCav1 to a novel neurodegenerative mouse model of a familial form of AD.
“These results suggest that SynCav1 gene therapy is an attractive approach to restore brain plasticity and improve brain function in AD and potentially in other forms of neurodegeneration caused by an unknown etiology,” the researchers noted. They concluded that the results of this study and previous studies indicate that “… regardless of the cause of the neurodegenerative disorder (known or unknown etiology, injury or genetic defect), the therapeutic and translational potential of SynCav1 could be exploited at the future to treat sporadic cases. neurodegenerative diseases or for use in combination with already existing drugs or biologics designed to target known monogenic candidates linked to other neurodegenerative diseases (EOFAD, FALS, Parkinson’s and Huntington’s diseases).
The ability of SynCav1 to preserve axonal myelin in hippocampal neurons in PSAPP mice further indicates the potential utility of treatment for demyelinating diseases, including multiple sclerosis, Gillian-Barre syndrome, and disease. Charcot-Marie-Tooth, the scientists noted.
Head’s laboratory is currently testing the administration of the SynCav1 gene in other models of AD in symptomatic stages as well as in a mouse model of amyotrophic lateral sclerosis (Lou Gehrig’s disease). He hopes to advance this work towards human clinical trials soon. SynCav1 gene therapy is patented by UCSD and the Department of Veterans Affairs.