- Alzheimer’s disease is the most common cause of dementia, responsible for up to 80% of dementia cases worldwide.
- The causes are highly complex, with many of the symptoms thought to be caused by the build up of two proteins — beta-amyloid and tau — in the brain.
- Most drug research focuses on these two proteins, but new research suggests that drugs targeting DNA strand breaks and inflammation that are seen early in Alzheimer’s may be another treatment option.
- In a mouse model, KCL-286, a drug that has passed phase 1 trials for spinal injuries in people, repaired DNA breaks and reduced inflammation.
Alzheimer’s disease, which causes 60–80% of all dementia cases, is a progressive disease that affects memory, thinking and behavior, and there are currently few effective therapies.
It is characterized by a build up of two proteins in the brain. One, beta-amyloid, builds up in the spaces between nerve cells; the other, tau, collects within nerve cells.
Both are thought to interfere with the functioning of, and communication between, nerve cells, leading to a decline cognitive function and other symptoms of Alzheimer’s disease.
Until now, treatment has focused on alleviating symptoms and, more recently, disease-modifying therapies that remove amyloid beta, which have led to improvements in cognitive function in some people.
Now, a study suggests that targeting DNA damage and inflammation in early-stage Alzheimer’s could be another treatment option.
The study, published in
Dung Trinh, MD, internist at the MemorialCare Medical Group and Chief Medical Officer of Healthy Brain Clinic in Irvine, CA, not involved in the study, told Medical News Today:
“This is a potentially significant finding because it points to a different way of thinking about Alzheimer’s disease. Rather than focusing exclusively on amyloid or tau, KCL-286 appears to act on neuronal DNA damage and neuroinflammation — two processes that may begin relatively early in the disease.”
The researchers investigated the effect of KCL-286, a drug that can pass through the
In the early stages of Alzheimer’s disease, these breakages are common, and a first stage of neuron damage that can lead to cognitive decline and other symptoms.
In the mouse model, researchers gave KCL-286 to mice genetically modified to produce amyloid plaques, and wild-type mice.
All the mice were male, and there were three in each treatment group. From the age of 15 to 18 months, the mice were given three injections a week of either 1mg/kg of KCL-286 or placebo, which was 80% dimethyl sulfoxide in distilled water.
After euthanising the mice at 18 months old, researchers removed their brains for analysis. The brains were coded so analysts did not know whether they were from treatment or placebo mice.
In the genetically modified mice given KCL-286, more neuronal double-strand breaks were repaired. This was partly due to upregulation of BRCA1, but the analysts also saw the repairs where there was not an increase in BRCA1 activity. The drug also modified the activity of microglia and astrocytes, cells that are involved in nerve inflammation.
Steven Allder, MD, a consultant neurologist at Re:Cognition Health, likewise not involved in this study, commented that:
“If this is replicated in humans, it could represent an entirely new therapeutic strategy that supports existing disease-modifying treatments. However, it’s important to remember that these results are currently preclinical, and many therapies that show promise in animal models do not ultimately translate into successful treatments for patients.”
The changes were more evident in the cortical areas of the brain than in the hippocampus, an area vital to memory, which is increasingly damaged as Alzheimer’s progresses. This suggests that the drug may be more effective in the earlier stages of Alzheimer’s.
Trinh explained the potential of the treatment, saying:
“One of the most intriguing aspects of this research is the possibility of intervening before extensive and irreversible neuronal loss has occurred. DNA damage and inflammatory changes may arise early in the Alzheimer’s disease process, so strengthening neuronal repair mechanisms while reducing harmful inflammatory activity could represent a new disease-modifying strategy.”
“It may ultimately prove useful as an additional treatment rather than a replacement for amyloid- or tau-directed therapies,” he added.
“Alzheimer’s disease involves several interacting mechanisms, and the future may lie in combination treatment — similar to the way we manage cardiovascular disease or cancer — selected according to an individual patient’s biology and stage of disease,” noted Trinh.
The study authors suggest that the treatment could have potential as a disease-modifying therapy by targeting early DNA damage and inflammation, but the findings would have to be replicated in people.
Trinh told MNT that he would like to see the findings independently replicated in Alzheimer’s models with significant tau pathology and models that more closely reflect sporadic late-onset disease, adding that “researchers need to demonstrate a clear dose-response relationship, adequate penetration into the brain and durable effects after treatment.“
“It will also be important to assess long-term safety, because retinoic-acid receptor signaling can influence a wide range of biological processes,” he noted.
He further emphasized that the most important next step would be a carefully designed clinical study in people with early, biomarker-confirmed Alzheimer’s disease.
Allder called the proposed mechanism particularly interesting, as “it targets the protein tyrosine phosphatase sigma (PTPσ) receptor, which is involved in limiting nerve repair following injury.“
“By blocking this pathway, the treatment appears to encourage neuronal regeneration, enhance synaptic plasticity and reduce neuroinflammation — processes that are increasingly recognised as important in Alzheimer’s disease as well as spinal cord injury,” he explained.
However, he cautioned that: “While such a regenerative approach is scientifically compelling, manipulating pathways involved in nerve growth and repair is complex. Larger clinical studies will be needed to establish both long-term safety and whether the biological effects observed in laboratory models translate into meaningful improvements in cognition and daily functioning.”
“Future treatment is likely to involve combination approaches that target multiple aspects of the disease, including amyloid, tau, inflammation, synaptic dysfunction and the brain’s ability to repair itself. Studies such as this broaden our knowledge of possible therapeutic targets and reinforce the significance of ongoing exploration of innovative regenerative strategies. Although it is still early days, this research showcases the exciting direction in which Alzheimer’s science is moving.”
– Steven Allder, MD
