AGE/DOSE
Brain & Neurons

Israeli Scientists Find Potential Breakthrough Drug for Alzheimer’s

Cognitive deficits, neurodegeneration, and neuroinflammation are prevented in an Alzheimer’s mouse model with a new drug that targets VDAC1 — a protein that transports molecules like NAD+ to and from mitochondria.

By Daniel R. Miranda, Ph.D.

Key Points: 

  • A freshly developed drug called VBIT-4 prevents learning and memory deficits in Alzheimer’s mice. 
  • VBIT-4 stops mitochondria-associated neuron death, indicating the prevention of neurodegeneration. 
  • Inflammation of the brain (neuroinflammation), implicated in triggering Alzheimer’s, is prevented by VBIT-4. 

Someone develops Alzheimer’s disease (AD) every 66 seconds in the United States. However, we still don’t know what triggers this neurodegenerative disease. Now, researchers from the Ben-Gurion University of the Negev in Israel have clued in on a protein called VDAC1. VDAC1 is embedded within the walls of mitochondria and transports a multitude of molecules, including NAD+. Moreover, VDAC1 has the power to evoke inflammation and programmed cell death — apoptosis. 

As reported in Translational Neurodegeneration, Verma and colleagues demonstrate that targeting VDAC1 with a drug called VBIT-4 prevents many of the symptoms and brain dysfunction associated with AD. By placing 20 mg/kg of VBIT-4 in the drinking water of AD mice, the Israeli scientists were able to prevent memory loss and neurodegeneration, the most prominent features of AD. They also prevented neuroinflammation with VBIT-4, pointing to inflammation as an AD trigger.   

Inhibiting Mitochondrial Dysfunction Prevents Alzheimer’s Symptoms 

To test the effects of VBIT-4, Verma and colleagues gave 20 mg/kg of the drug to 5xFAD mice, a well-studied mouse model for AD. The AD mice were then subjected to a series of behavioral tests to assess their learning and memory. One of these tests called the radial arm water maze, involved the mice learning to navigate and remember the location of an escape platform. 

During the maze test, AD mice that did not receive VBIT-4 made nearly twice as many errors and took twice as long to find the platform as normal mice. However, AD mice given VBIT-4 did just as well as normal mice on the test. These findings suggest that treatment with VBIT-4 prevents learning and memory deficiencies associated with AD mice. 

VBIT-4 Prevents Cognitive Dysfunction: Radial Arm Water Maze Test Results. Alzheimer's mice (5XFAD) exhibit increased errors (left) and longer navigation times (right) compared to normal mice (WT), indicating impaired learning and memory. However, treatment with VBIT-4 (5XFAD + VBIT-4) significantly mitigates cognitive dysfunction.
(Verma et al., 2022 | Transl. Neurodegener.) VBIT-4 Prevents Cognitive Dysfunction. Compared to normal mice (WT), Alzheimer’s mice (5XFAD) make twice the errors (left) and take twice as long (right) to navigate the radial arm water maze, indicating deficits in learning and memory. However, this cognitive dysfunction is largely prevented by treatment with VBIT-4 (5XFAD + VBIT-4).

Once the behavioral tests were completed, Verma and colleagues examined the mice’s brains for signs of neurodegeneration. To conduct this examination, Verma and colleagues measured a protein called synaptophysin, which is only found in neurons. They found a 3-fold decrease in synaptophysin in the brains of untreated AD mice. In contrast, AD mice treated with VBIT-4 did not exhibit a reduction in this protein, suggesting the prevention of neurodegeneration. 

VBIT-4 Prevents Neuronal Loss: Synaptophysin Levels in Alzheimer's Mice (5XFAD) Compared to Normal Mice (WT). Alzheimer's mice exhibit a 3-fold decrease in synaptophysin, a protein marker for neurons. However, treatment with VBIT-4 (5XFAD + VBIT-4) prevents this neuronal loss.
(Verma et al., 2022 | Transl. Neurodegener.) VBIT-4 Prevents the Loss of Neurons. Compared to normal mice (WT), Alzheimer’s mice (5XFAD) showed a 3-fold decrease in synaptophysin, a protein marker for neurons. However, this was prevented by treatment with VBIT-4 (5XFAD + VBIT-4).

VBIT-4 works by preventing VDAC1 from forming a large channel within the outer wall of mitochondria. It is this large hole that allows various factors to be released from the mitochondria and activate inflammation and apoptosis. While Verma and colleagues showed that apoptosis and neuron loss was mitigated by VBIT-4, they further investigated whether VBIT-4 could prevent inflammation. 

To assess inflammation, the researchers measured various factors, including a protein called NF-𝜅B-p65. They found that the mRNA for NF-𝜅B-p65 was dramatically increased in the brains of untreated AD mice.  However, AD mice treated with VBIT-4 did not display this increase. These findings suggest that VBIT-4 treatment can prevent features of neuroinflammation in AD mice. 

VBIT-4 Prevents Neuroinflammation: NF-𝜅B-p65 mRNA Levels in Alzheimer's Mice (5XFAD) Compared to Normal Mice (WT). Alzheimer's mice exhibit a 150-fold increase in NF-𝜅B-p65 mRNA, a genetic marker of inflammation. However, treatment with VBIT-4 (5XFAD + VBIT-4) prevents neuroinflammation.
(Verma et al., 2022 | Transl. Neurodegener.) VBIT-4 Prevents Neuroinflammation. Compared to normal mice (WT), Alzheimer’s mice (5XFAD) showed a 150-fold increase in NF-𝜅B-p65 mRNA, a genetic marker of inflammation. However, this was prevented by treatment with VBIT-4 (5XFAD + VBIT-4).

Targeting Mitochondrial Health to Counter Aging  

VBIT-4: A Future Anti-Aging Drug?

Overall, the findings of Verma and colleagues suggest that VBIT-4 prevents much of the symptoms and brain pathology associated with AD by preventing VDAC1 proteins from forming an apoptosis and inflammation-mediating channel in mitochondria. If held up in future animal and human studies, these findings could revolutionize the way AD patients are treated. 

Furthermore, Verma and colleagues have previously shown that VBIT-4, and another one of their drugs called VBIT-12 prevent mitochondrial dysfunction and apoptosis in mouse models for type 2 diabetes, lupus, and colitis. This could mean that these VBIT drugs, targeting the so-called gatekeeper of mitochondria, VDAC1, could potentially treat these diseases in the future if these findings can be translated to humans. 

Current Interventions for Targeting Mitochondrial Health

Mitochondrial dysfunction is a hallmark of aging, meaning that it underlies several chronic age-related conditions, including neurodegeneration. Our mitochondria produce cellular energy and are thus critical for cell survival and ultimately organ and tissue function. As we age, our mitochondria tend to become less efficient, leading to their dysfunction. 

Age-Related Mitochondrial Decline: Electron Transport Chain (ETC) Activity and Reactive Oxygen Species (ROS) Production. In middle age, increased ETC activity indicates mitochondria working harder, resulting in elevated ROS production. With advancing age, mitochondria struggle to sustain this increased activity, leading to damage in mitochondrial DNA (mtDNA) and proteins.
(Madreiter-Sokolowski et al., 2018 | Genes) Age-Related Mitochondrial Decline. Beginning in middle age, our mitochondria become less efficient and need to work harder, as shown by increased electron transport chain (ETC) activity. However, this leads to increased reactive oxygen species (ROS) production. In old age, our mitochondria can longer keep up their increased activity, damaging mitochondrial DNA (mtDNA) and proteins. 

It may be possible to slow the deterioration of our mitochondria with several strategies, including diet and exercise. For example, caloric restriction — consuming fewer calories by eating less food — has been shown to increase the energy produced by mitochondria. Furthermore, exercise has been shown to improve muscle mitochondrial health, which may aid in countering the age-related decline in muscle strength and size — sarcopenia. Pharmacological interventions that have been shown to improve mitochondrial health or counter ROS include senolytics, NAD+ precursors, and polyphenols like resveratrol. 

Model & Dosage

Model: 5xFAD Alzheimer’s model mice

Dosage (oral): 20 mg/kg VBIT-4

Source

Verma A, Shteinfer-Kuzmine A, Kamenetsky N, Pittala S, Paul A, Nahon Crystal E, Ouro A, Chalifa-Caspi V, Pandey SK, Monsonego A, Vardi N, Knafo S, Shoshan-Barmatz V. Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology. Transl Neurodegener. 2022 Dec 28;11(1):58. doi: 10.1186/s40035-022-00329-7. Erratum in: Transl Neurodegener. 2023 Jan 11;12(1):2. PMID: 36578022; PMCID: PMC9795455.

References

Madreiter-Sokolowski CT, Sokolowski AA, Waldeck-Weiermair M, Malli R, Graier WF. Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction. Genes (Basel). 2018 Mar 16;9(3):165. doi: 10.3390/genes9030165. PMID: 29547561; PMCID: PMC5867886.

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