Mouse Study: Follicle-Stimulating Hormone Is a Key Instigator of Alzheimer’s Disease

A study published in Nature reports that Follicle-Stimulating Hormone (FSH) may be a key instigator of Alzheimer’s disease (AD). Treatment including gene therapy and anti-FSH antibodies reversed and prevented AD-related pathologies in mice.


Alzheimer’s disease (AD) is the 7th leading annual cause of death in the United States and is typically caused by an abnormal buildup of two proteins: amyloid and tau. Amyloid proteins help with neuron growth and repair but can destroy nerve cells later in life due to abnormal buildups referred to as plaques. Tau is intended to stabilize neurons by providing them with a  neurofibrillary structure. When unregulated, tau proteins can dysfunctionally aggregate into neurofibrillary tangles (NFTs), causing AD.

Elevated follicle-stimulating hormone (FSH) levels are often associated with menopause and, when regulated, the hormone’s intended purpose in the human body is to stimulate egg and sperm development. Both low and high levels of FSH are associated with infertility and sexual defects.

Scientists have long suspected that menopause plays a role in the pathogenesis of AD. During menopause, females have elevated levels of FSH, which—among other hormones—can lead to bone decay, weight gain, tiredness, and cognitive defects like those observed in AD patients. Women have a three-times higher rate of disease progression.

Method & Results

To determine if FSH is linked to the development of AD, researchers from Emory University and Icahn School of Medicine conducted an experiment in which they manipulated FSH levels in mice and then examined cognitive function and plaque formation.

In mice injected with extra FSH for three months, researchers already observed amyloid plaques and and tau NFTs, as well as inflammation and destruction of neurons—all symptoms of AD. Specifically, the damage, plaques, and NFTs occurred largely in hippocampal and cortical neurons. Further, these mice showed impaired spatial memory as demonstrated by comparatively poor performance in a water maze test. These changes were observed in both male and female mice.

The researchers then administered an antibody drug that lowers FSH levels. After treatment, they identified that the same AD symptoms identified in the FSH-supplemented mice had nearly disappeared. Their anti-FSH antibody (FSH-Ab) inhibited amyloid plaque and NFT formation while also reversing cognitive decline. As FSH-Ab inhibits all functions of FSH, the mice would also experience increased bone mass, decreased body fat, and increased energy expenditure.

The researchers believe excess FSH causes an increase in the expression of a gene that regulates an enzyme called arginine endopeptidase. This enzyme ultimately keeps amyloid and tau proteins in check, but once overproduced, clumping and tangling can begin. Experimentation revealed that either the deletion of this gene via gene therapy or FSH-Ab treatment successfully reduced amyloid plaques and tau NFTs and improved water maze performance.

While increased FSH levels in menopausal women is implied in the pathogenesis of AD, the researchers tested how male mice would respond to FSH-Ab. They found that the antibody “at the very least” prevented amyloid accumulation in the male mice.


The researchers concluded that extremely high FSH levels can impact protein regulation pathways, eventually leading to AD-related pathologies in mice. Also, antibody therapy targeting FSH can reverse and prevent formation of amyloid plaques and NFTs. Mice had recovered performance in cognitive tests following FSH-Ab treatment.

These findings have serious implications if the findings translate to humans. FSH concentrations could be used as an assay in patients to determine pathology and treatment. Antibody and gene therapies that proved to reverse and prevent AD symptoms in mice could also be used in humans with FSH-induced AD.

  • Abbott, A. (2022, March 9). Could drugs prevent Alzheimer’s? These trials aim to find out. Nature.
  • Murphy, S. L., et al. (2021, December). National Center for Health Statistics.
  • Orlowski, M., & Sarao, M. S. (2021, May 9). Physiology, follicle stimulating hormone. National Center for Biotechnology Information.
  • Xiong, J., Kang, S., et al. (2022, March 2). FSH blockade improves cognition in mice with Alzheimer’s disease. Nature.

Transparent Zebrafish Study Reveals How Sleep Repairs Damaged Neuronal DNA

Using transparent zebrafish, Israeli researchers were able to confirm neuronal DNA repair as a function of sleep, also identifying a protein that triggers both DNA repair and sleep.


The functions of sleep, though widely researched, have largely remained a mystery. It is known that sleep influences cognition, benefitting learning and memory, but proposed physiological functions have had little strong evidence. Proposed functions of sleep include removing toxic byproducts in the brain caused by wakefulness, replenishing energy and supplies for cells, and remediating neural damage and cellular stress.

Prior research showed that wakefulness and neuronal activity causes DNA double-strand breaks. These lesions are accumulated during wakefulness, contributing to homeostatic sleep drive (the pressure to sleep that builds up as time awake increases). Sleep has been demonstrated to decrease this DNA damage.

Researchers from Israel’s Bar-Ilan University and Tel Aviv University used zebrafish to study neuronal DNA repair as a potential novel function of sleep. The zebrafish is a tiny freshwater fish that has been widely used as a model organism due to their 70% genetic homology (similarity) to humans. Among other parallel physiologies, zebrafish exhibit a diurnal sleep cycle with states closely resembling mammalian slow-wave sleep (SWS) and rapid eye movement (REM) sleep. A mutated type of zebrafish is transparent, enabling researchers to observe the previously unobservable.

Confocal microscopy image showing the developing face of a 6 day old zebrafish larva. / Oscar Ruiz and George Eisenhoffer, University of Texas MD Anderson Cancer Center

By inducing neuronal DNA damage in zebrafish, they were able to determine its relation to sleep as well as causal proteins.


First, the researchers confirmed a significant positive correlation between levels of neuronal DNA damage and total sleep time (R = 0.76). During wakefulness, zebrafish larvae were treated with pentylenetetrazol, which stimulated their neuronal activity. Consequently, the larvae had increased neuronal DNA damage and a 5-fold increase in total sleep time.

Because neuronal DNA damage is not only caused by cell activity, the researchers then exposed the larvae to UV radiation, which damaged their DNA without increasing their neuronal activity. Their subsequent increased sleep further confirmed that DNA damage was the cause.

By testing the rates at which genes involved in the DNA damage response (DDR) were expressed during sleep, they found that the RAD52 and Ku80 proteins were responsible for repairing double-strand breaks during sleep.

Further analysis uncovered that the PARP1 protein, a DNA damage detector that organizes the DDR, was immediately recruited and activated upon neuronal DNA damage.

When the researchers provoked greater expression of PARP1, total sleep time and depth increased—demonstrating that the protein is what connects the DNA damage response to homeostatic sleep drive. PARP1 was also shown to promote sleep regardless of damage.


The study confirms in multiple experiments that neuronal DNA repair is a function of sleep regulated by the PARP1 enzyme and carried out by the DNA repair proteins RAD52 and Ku80.

Triggering neuronal DNA damage via cellular excitation and UV light both caused the expected result of increased sleep, with PARP1 as the protein responsible for detecting the damage, provoking a repair response, and causing increased sleep drive.

The study authors noted their intrigue that FDA-approved PARP1 inhibitors used as antitumor agents all caused fatigue as the prominent side effect, suggesting that inhibiting PARP1 masks its sleep-promoting signals. The use of PARP1 inhibitors was also found to cause increased DNA damage. These results, separate from their study, align with their findings regarding the functions of PARP1 as observed in zebrafish.

  • Frank, M. G. (2006, August 1). The mystery of sleep function: Current perspectives and future directions. De Gruyter.
  • Yourgenome. (2021, July 21). Why use the zebrafish in research?
  • Zada, D., et al. (2021, December 16). Parp1 promotes sleep, which enhances DNA repair in neurons. Molecular Cell.

New Stem Cell Mechanism Behind Down Syndrome Discovered, Paves Way for Treatment

A team of researchers from MIT’s Alana Down Syndrome Center published results in Cell Stem Cell that pointed to a mechanistic link between Down syndrome (DS) and genome-wide transcriptional disruption. The team, led by Hiruy Meharena, revealed that senescence (the state when cells stop dividing) may play an important role in the progression of down syndrome and could lead to novel therapeutic approaches for treating individuals with DS.

Down syndrome, also known as trisomy 21 (T21), is a congenital disorder that is caused by the triplication of  the 21st chromosome. Previous studies have linked the cognitive deficits of the disorder to a lack of dysfunctional neural progenitor cells (NPCs). These are the stem cells that differentiate into glial and neuronal cells which make up the central nervous system. Neurogenesis, the process in which new neurons are formed in the brain, was found to be significantly reduced in the brains of mice with DS because the lack of NPCs ultimately led to a decrease in cortical matter.

Another study linked T21 to transcriptional disruption in human-derived induced pluripotent stem cells (or iPSCs). His research team found that the disruption to those cells was also consistent with other papers that examined related aneuploidies. Nonetheless, while both studies did reveal a connection between T21 and the cells, they did not delve into the factors that caused this relationship.

As a result, Meharena’s study explores a potential mechanism that may explain how this transcriptional disruption may take place. His team examined T21’s effect on DS-related iPSCs and NPCs at the genetic, epigenetic and mRNA levels. Their finding revealed that although the iPSC were not significantly affected, the NPCs that were derived from these iPSCs revealed significant chromosomal introversion and disrupted lamina-associated domains. This made it so that the squished chromosomes would have increased genetic interactions within itself but decreased interactions with the other chromosomes. Additionally, they found decreased NPC’s chromatin accessibility to the A-compartment, which is associated with transcriptional downregulation, and increased accessibility to the B-compartment, which is associated with transcriptional upregulation.

What was notable was that these changes of differentially expressed genes of NPCs shared many qualities with cells that became senescent via oxidative stress conditions. Furthermore, senolytic pharmaceutical treatments of dasatinib and quercetin was found to ease some of the transcriptional disruption and deficiencies that arose from T21 affected NPCs. The use of these drugs not only improved gene accessibility and transcription but also helped with cellular migration and proliferation.

Although this treatment is not practical due to the neutropenic (neutrophil-decreasing) side effects of dasatinib, it stills elucidates a previously unknown avenue for research into potential treatments to be conducted. With Down syndrome being one the most common intellectual disabilities, having a stronger understanding of the mechanisms behind its progression may provide an opportunity to restore or prevent some of the dysfunctions of the disease. Although this research is only a small piece to the larger puzzle that is DS, it still provides a step to better understanding the condition, hopefully one day assisting individuals with the disorder and their families.