Could a nasal spray help fight Alzheimer’s disease in the future?

Like other forms of dementia, Alzheimer’s disease results from the death of brain cells, making it a neurodegenerative condition characterized by gradual brain cell loss.

Tau is a protein associated with microtubules in the human brain, aiding in the stabilisation of microtubules, which are important for maintaining the cell’s shape and organisation in neurons.

In a healthy brain, tau proteins ensure proper cellular order.

However, in neurodegenerative diseases, tau proteins can become abnormally twisted, forming tangles that interfere with neuronal function and cause cognitive decline.

In individuals with Alzheimer’s disease, the brain tissue progressively loses nerve cells and connections, while small deposits called plaques and tangles accumulate on the nerve tissue.

Plaques, composed of a protein called beta-amyloid, form between dying brain cells, while tangles, made up of tau, develop within the nerve cells.

The exact cause of these changes remains unclear, though multiple factors may contribute to their occurrence.

Existing tau immunotherapies have faced challenges in effectiveness due to their limited capacity to penetrate the intracellular compartments where these tau accumulations are located.

In the new study, an intranasal antibody treatment has shown promise in targeting, dismantling, and preventing the spread of tau protein.

The buildup of tau protein inside neurons is linked to Alzheimer’s and other neurodegenerative conditions and engineering antibodies to selectively attack tau may help clear this build up and enhance cognitive function.

However, tau antibody treatments are still in the development stage and have had limited success in clinical trials.

In this study, researchers introduced a monoclonal tau antibody named toxic tau conformation–specific monoclonal antibody-2 (TTCM2), which specifically targeted pathological tau deposits in post mortem brain tissue from patients with Alzheimer’s, dementia with Lewy bodies and progressive supranuclear palsy.

TTCM2 also inhibited the seeding activity of patient-derived tau oligomers in tau biosensor cells, indicating its potential to prevent the spread of tau fibrils among neurons.

Further tests showed that TTCM2 was effective when delivered via lipid molecule compartments, or micelles, through the noses of aged mice with tauopathy.

According to the study, a single one dose of TTCM2 micelles was sufficient to disperse throughout the brains of the mice, reduce tau pathology and improve cognition.

Investigating the mechanisms behind TTCM2’s efficacy, researchers found that the antibody interacts with an intracellular receptor known as tripartite motif-containing 21 (TRIM21).

The researchers note that their findings align with a recent study showing that TRIM21 is essential for effective tau immunotherapy.

First author Sagar Gaikwad, PhD, from the Department of Neurology at The Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, explained the key findings to Medical News Today.

“Our study shows that the nasal tau immunotherapy importantly reverses Alzheimer’s pathology in mice and a single dose is enough to achieve this,” Gaikwad explained. “This also improves memory and behavior in aged mice.”

“Importantly, our TTCM2 antibody effectively recognizes and neutralizes pathological tau in the brain tissues from patients with Alzheimer’s disease. This research could lead to new treatments that improve quality of life and potentially reverse or delay the onset of severe symptoms in patients with Alzheimer’s disease and related dementia.”

– Sagar Gaikwad, PhD

Jason Krellman, PhD, an associate professor of neuropsychology in the Department of Neurology at Columbia University Irving Medical Center, not involved in this study, told MNT that “we’ve known for many years that dysfunction of tau is a prominent feature of neurodegenerative diseases such as Alzheimer’s.”

“Relatedly, the amount of dysfunctional tau in the brain correlates positively with the severity of cognitive impairment in people with Alzheimer’s disease,” he added. “Therefore, treatments to reduce tau have been a major focus of research.”

Krellman explained what the recent study achieved:

“The researchers used an immunotherapy treatment that reduces the amount of dysfunctional tau in the brains of mice as well as prevents the production of ‘tau seeds,’ which allow the dysfunction to spread through the brain. Getting such treatments into the brain has been challenging because of the blood-brain barrier, the brain’s protective blockade against numerous but not all outside substances. The researchers managed to circumvent this barrier by using a novel method of administration, delivery through the nose to be sure absorption by the brain was rapid and more complete.”

The expert found the results of this animal study encouraging.

He noted that it is “especially promising was that the mice showed improvement in cognitive function via their behavioral responses in tests that assess recognition memory and spatial awareness.”

Kubanych Takyrbashev, MD, health and wellness advisor at NAO, also not involved in the research, agreed, noting that the study “addresses a critical challenge in the field of neurodegenerative diseases.”

“Developing a conformation-specific antibody for tau that can selectively target toxic tau aggregates is a significant advancement. What makes this study particularly compelling is the innovative delivery method: Using lipophile micelles for intranasal administration. This method effectively bypasses the blood-brain barrier, a major hurdle in treating neurological disorders,” Takyrbashev explained.

He pointed out that “the antibody’s ability to specifically target and reduce toxic tau aggregates while also improving cognitive function in tauopathy mice demonstrates a promising approach to tackling tau-related pathologies.”

“The study’s findings are encouraging and open up new avenues for therapeutic development” because “[t]his research enhances our understanding of tau pathology and highlights a practical and potentially transformative strategy for delivering therapeutic agents directly to the brain,” said Takyrbashev.

Krellman noted that “it’s tempting to look at this research and imagine that one day we will have a widely available nasal vaccine for Alzheimer’s disease.”

“However,” he cautioned, “even though mice can be excellent animal models in which to study new potential treatments for humans, there are obviously some vast differences between mice and humans,” emphasizing the need to replicate these findings in a human clinical trial.

“Further research is needed because human brains are much larger than mouse brains, meaning that diffusion of the treatment through the human brain might not unfold as effectively as in the mouse brain. There could be subtle biological differences in efficiency of metabolism and treatment side effects between mice and humans. Similarly, human cognition and behavioral responses are significantly more complex than that of mice, and so we cannot be certain the treatment would have a clinically significant effect on human cognition, nor do we yet know how long any beneficial effect might last.”

– Jason Krellman, PhD

In conclusion, Krellman said: “We have a lot more work to do in this area, but this research and others like it should give people hope that we are making progress toward understanding how to intervene and stop the pathological progression of Alzheimer’s disease so we can one day develop effective treatments.”