Sex differences in Alzheimer’s linked to protein that blocks brain cell growth

Recent research has identified a specific biological mechanism that may explain why females experience more severe impairments in brain cell regeneration associated with Alzheimer’s disease. The findings, published in the journal Biology of Sex Differences, suggest that a family of signaling proteins becomes overactive in the female brain and suppresses the growth of new neurons. This study indicates that blocking these proteins could offer a potential strategy for restoring brain function in patients.

Alzheimer’s disease affects a substantial portion of the aging population. In the United States alone, the prevalence of the condition has exceeded 7 million individuals. A distinct disparity exists within these numbers. Women account for nearly two-thirds of the affected population. This difference persists even when accounting for the fact that women generally live longer than men.

The biological drivers behind this susceptibility have remained largely elusive. Researchers are working to understand how sex-specific biological processes interact with the pathology of the disease.

A primary area of interest is the hippocampus. This region of the brain is essential for learning and memory. It is also one of the few areas where the adult brain can generate new neurons. This process is known as neurogenesis. In patients with Alzheimer’s disease, this regenerative ability is severely compromised. The failure to replace or repair neural connections contributes to cognitive decline.

Previous investigations have pointed to a group of signaling molecules called bone morphogenetic proteins, or BMPs. These proteins are vital during early development for establishing the body’s architecture.

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However, in the aging brain or in diseased states, their presence can be detrimental. Elevated levels of certain BMPs have been observed in the brains of patients with Alzheimer’s disease. These elevated levels appear to correlate with a halt in the production of new brain cells.

A research team from Waseda University and the RIKEN Center for Brain Science in Japan sought to determine if these proteins play a role in the sex differences observed in the disease. The study was led by Xingyu Su, a doctoral student at Waseda University, under the supervision of Dr. Toshio Ohshima.

The team hypothesized that BMP signaling might function differently in males and females. They also sought to determine if these differences directly impacted the brain’s ability to regenerate.

To investigate this, the researchers utilized a specific mouse model of Alzheimer’s disease known as APPNL-G-F. Many traditional mouse models rely on the artificial overexpression of amyloid precursor protein. This can sometimes lead to physiological artifacts that act as confounding variables.

The APPNL-G-F model is a “knock-in” model. This means the mice express humanized amyloid-beta sequences at physiological levels. This approach provides a more accurate reflection of how the pathology develops in a natural biological context.

The researchers analyzed the hippocampi of these mice at six months of age. They measured the levels of various BMP molecules. They compared these levels against those found in healthy, wild-type mice of the same age. The analysis focused on gene expression to see which BMPs were being produced more aggressively.

The results showed a clear distinction between the sexes. The female Alzheimer’s model mice exhibited higher expression levels of BMP family members, specifically BMP4, BMP6, and BMP7. While the male mice also showed some elevation compared to healthy controls, the increase was much more pronounced in the females.

Simultaneously, the team examined the rate of neurogenesis. They looked for specific markers that indicate cells are dividing and growing. One such marker is a protein called PCNA, which appears in cell nuclei during replication.

Another is doublecortin, or DCX, which helps identify immature neurons. The female mice showed a marked reduction in these markers compared to the males. This indicated that the process of generating new neurons was more severely inhibited in the female brain.

The correlation was strong. The mice with the highest levels of BMPs had the lowest levels of new neuron growth. This suggested a direct link between the two phenomena. The researchers posited that the overactive BMP signaling was acting as a brake on the neural stem cells. This prevented them from proliferating and differentiating into functioning neurons.

To confirm this causal relationship, the team performed a rescue experiment. They treated the female Alzheimer’s model mice with a drug named LDN193189. This compound is known to inhibit the signaling pathway used by BMPs. The mice received daily injections of the inhibitor for three weeks. Following the treatment, the researchers examined the brain tissue again.

The inhibition of BMP signaling produced a positive outcome. The number of dividing stem cells in the hippocampus increased. The levels of neurogenesis in the treated female mice were restored to levels comparable to those seen in healthy, wild-type mice. This demonstrated that the suppression of neurogenesis was reversible. It also confirmed that BMP signaling was the primary driver of this impairment in the female mice.

The researchers also explored why these differences might exist. They turned their attention to estrogen. Estrogen is the primary female sex hormone. To study its effects, they utilized a mouse nerve cell line called Neuro2a. These cells are useful for laboratory experiments because they possess estrogen receptors.

The team exposed these cells to estradiol. This is a potent form of estrogen. They then measured the resulting changes in gene expression. The stimulation caused a distinct rise in the levels of BMP6. It also increased the levels of a transcription factor called TFAP2B, which regulates BMP expression.

This finding presents a complex biological picture. Estrogen is typically considered neuroprotective. In many contexts, it supports the health and survival of neurons. However, this study indicates that in the specific context of Alzheimer’s pathology, estrogen signaling might drive the upregulation of BMPs. This upregulation subsequently inhibits the generation of new neurons.

The team also conducted a separate experiment to see if acute injury caused the same sex-dependent results. They injected amyloid-beta peptides directly into the brains of normal mice. This caused immediate damage and increased BMP levels.

However, in this acute model, there was no difference between males and females. Both sexes suffered equal impairment. This suggests that the sex differences observed in the genetic model are likely due to long-term, chronic physiological processes involving hormones.

There are caveats to these findings. The study was conducted in mice. While the genetic model is advanced, it does not perfectly replicate human biology. The interaction between estrogen and BMPs is likely nuanced. In humans, Alzheimer’s disease is most common in post-menopausal women who have lower estrogen levels. The researchers suggest that dysregulation of estrogen signaling pathways, rather than simple levels of the hormone, may be at play.

Additionally, the researchers measured cell proliferation using specific markers. While this indicates that cells are dividing, it does not fully track the long-term survival of these new neurons.

Future research will need to determine if these new cells mature and integrate into the brain’s circuitry to improve memory function. The team also noted that while neurogenesis improved, they did not measure the effect on amyloid plaques or other disease markers in this specific study.

The study opens new avenues for therapeutic development. Current treatments for Alzheimer’s disease often focus on removing amyloid plaques. This research highlights the potential of targeting the brain’s regenerative capacity.

Drugs that modulate BMP signaling could potentially serve as a complementary therapy. Such an approach would aim to maintain the brain’s ability to repair itself even as the disease progresses.

This work underscores the importance of considering sex as a biological variable in medical research. Mechanisms of disease can differ fundamentally between males and females. Understanding these differences is essential for developing effective treatments for all patients.

“Our study provides new insights into the role of BMP signaling activation in impaired neurogenesis in AD, which will guide future translational research,” says Su. “Ultimately, this knowledge can lead to the development of novel intervention strategies, reducing the clinical and caregiving burdens associated with AD.”

The study, “Sex-related upregulation of bone morphogenetic protein signaling inhibits adult neurogenesis in APPNL−G−F alzheimer’s disease model mice,” was authored by Xingyu Su, Rina Takayanagi, Hiroki Maeda, Takaomi C. Saido, and Toshio Ohshima.