PSEN1 Mutations Trigger Brain Degeneration Independent of Beta-Amyloid

Post by Soumilee Chaudhuri

The takeaway

Mutations in the presenilin 1 (PSEN1) gene are a major cause of familial Alzheimer’s disease, commonly known as early-onset Alzheimer’s Disease (EOAD), which affects individuals below the age of 65. This study discovered that PSEN1 mutations can lead to neurodegeneration in the brain through pathways that do not involve Amyloid-beta (Aβ) accumulation — a well-known hallmark and the most commonly studied therapeutic target of AD. 

What's the science?

PSEN1 is part of γ-secretase, an enzyme that instructs precursor proteins like amyloid precursor protein (APP) to produce amyloid-beta (Aβ) peptides, which cause AD. Over 450 mutations in the PSEN gene have been linked to AD and while PSEN1 helps protect neurons, its mutations increase the ratio of the harmful and mutated Aβ (Aβ42) to non-mutated Aβ peptide (Aβ40) levels. Therefore, it's unclear whether these PSEN1 gene mutations cause AD by increasing the harmful Aβ42/ Aβ42 ratio or impairing the gene's protective functions. This week in PNAS, Yan and colleagues investigated whether a specific PSEN1 mutation (PSEN1 L435F), a severe familial AD mutation, causes age-related neurodegeneration independently of Aβ.

How did they do it?

The researchers engineered a mouse model carrying the PSEN1 L435F mutation, associated with EOAD, and bred it with mice lacking the amyloid precursor protein (APP) to reduce Aβ production in the offspring mice. Mice of both sexes, aged 2, 12, and 18 months old were used in this experiment, and detailed analyses of their brain tissue post-mortem allowed for the measurement of cortical atrophy, neuron loss, and other signs of neurodegeneration. Additionally, they also worked with several other mouse models that specifically deleted PSEN1 genes in brain cells. This setup allowed the researchers to investigate how these genetic changes impact neurodegeneration across different ages and different strains of mice all containing the PSEN1 mutation but lacking APP.

What did they find?

The researchers found that even with the APP deletion and Aβ absent, mice with the PSEN1 L435F mutation still developed significant cortical neurodegeneration, similar to that seen in AD in humans. The researchers also noted increased cell death and brain inflammation. Even with no Aβ production, these mice still experienced significant cortical volume reduction, neuron loss, increased cell death, and brain inflammation at all ages (2, 12, and 18 months). This suggests that the neurodegenerative processes in these mice are driven by alternative, non-amyloid pathways. 

What's the impact?

Mice with PSEN1 mutations exhibited severe neurodegeneration, synaptic impairment, and memory deficits, independent of amyloid beta levels. These findings challenge the amyloid-centric model of Alzheimer’s disease, particularly in cases involving PSEN1 mutations. Understanding these non-amyloid pathways could open up new avenues for treating Alzheimer’s by targeting alternative mechanisms of neurodegeneration. Despite extensive anti-Aβ therapeutic efforts, such as the approval of lecanemab, clinical outcomes have been modest. These findings emphasize the need for a broader understanding of AD, including the role of PSEN1 function, to develop more effective therapies.

Access the original scientific publication here

Altering the Stress Response To Reduce Anxiety

Post by Annie Phan

The takeaway

The most common mental health disorders, anxiety and depression, are linked to chronic stress. To design better pharmacological treatments for stress-related disorders, it is important to identify and undo the disruption of chemical interactions in the brain that occur with repeated exposure to stress.

What's the science?

Current medications for anxiety and depressive disorders target related neurotransmitter systems, like serotonin, to yield therapeutic effects. However, they also have side effects that may reflect biological processes unrelated to these disorders. This week in PNAS, Pandey and colleagues used mouse models of chronic stress to investigate signaling pathways that were changed in response to stress manipulation. Then, they attempted to reverse the anxiety behavior by pharmacologically repairing this pathway.

How did they do it?

The researchers used a mouse model of chronic stress where they physically restrained young adult mice for 3 hours daily for 14 consecutive days. They also validated their results with a second mouse model of stress, maternal separation, where young pups from postnatal day 5 to 21 were isolated from their mother for 3 hours daily. To assess the mice for anxiety- and depressive-like behaviours, they used common rodent assays like the elevated plus maze, marble burying test, and forced swim test. To study the molecular events in the brain specifically related to the synapse, they performed biochemical tests to evaluate the amount of relevant proteins and electrophysiological tests to evaluate excitatory and inhibitory transmission. To further investigate the reduction of protein expression, they performed a proteomic screen by co-immunoprecipitation and then mass spectrometry analysis, providing insight into how these proteins interact as part of a signaling pathway.  

What did they find?

First, the researchers found that following the chronic stress protocol, the mice in both chronic stress models showed anxiety and depressive-like behavior, and this was in parallel with the decrease in several inhibitory proteins at the synapse including Neuroligin2 (NL2). When they investigated the decrease in NL2 expression further, they found that upregulation of proteins including Src kinase and calmodulin (CaM) resulted in reduced interaction between MyosinVa (MyoVa) and NL2, indicating this pathway was altered in response to chronic stress. The authors manipulated this pathway by suppressing Src kinase activity via an injection of a Src kinase inhibitor, PP2 for 7 consecutive days after the chronic stress protocol. An inactive analog PP3 was used as a control. They observed a reduction in anxiety-like behavior in mice treated with PP2. Overall, inhibiting the elevated activity of Src kinase in chronically stressed mice re-established the expression of synaptic protein NL2 — which was previously reduced by stress — thereby restoring inhibitory synaptic transmission. 

What's the impact?

The public health burden of anxiety and depression calls for the need to create more effective and well-tolerated medication for these disorders. This study found a novel therapeutic target sensitive to the stress response, the Src-CaM-MyoVA-NL2 pathway, which is related to the GABA system responsible for inhibitory transmission. Targeting this pathway could help reduce anxiety behavior and improve outcomes for those affected. Further research in humans is needed to validate these findings and explore whether therapies targeting this pathway might be effective. 

ccess the original scientific publication here.

Orexin Neurons Mediate the Decision to Exercise Instead of Eating

Post by Shahin Khodaei

The takeaway

When mice are actively deciding between exercise or eating a tasty treat, the activity of a group of neurons in the lateral hypothalamus called orexin neurons plays a role in mice prioritizing exercise.

What's the science?

When given the choice between exercising or eating something, what part of the brain helps make the decision? One possibility is the lateral hypothalamus, an evolutionarily old region of the brain that plays a part in regulating both eating and movement. Specifically, research shows that a group of neurons called hypocretin/orexin neurons (HONs) in the lateral hypothalamus is important for these behaviours. What is not well-known is whether HONs also play a part in the decision between whether to eat or exercise. This week in Nature Neuroscience, Tesmer and colleagues published a study that looked at the role of HONs in this scenario and showed that the activity of these neurons played a part in mice prioritizing exercise over eating a highly palatable food.

How did they do it?

To study their decision-making process, the authors placed mice in the center of a maze with 8 arms. Each arm contained something different, giving the mouse multiple options to choose from (e.g. regular food, a new object, another mouse, etc.) Importantly, one arm contained a running wheel so mice could voluntarily exercise, and another arm was either empty or contained a tasty milkshake treat (the highly palatable food). This setup allowed the researchers to see if the mice chose exercise over the other options, particularly the milkshake.  

To parse out the role of HONs in this decision-making process, the authors either decreased or increased their function. They either injected mice with a pharmacological blocker for orexin receptors or increased the activity of HONs using a technique known as optogenetics. Tesmer and colleagues also used a technique called fiber photometry to indirectly measure the electrical activity of HONs. This let them see how the activity of these neurons changed when mice used the running wheel or ate the milkshake. 

What did they find?

When the authors placed the mice in the maze for 10 minutes, mice consistently chose to use the running wheel more than any other option, even when the maze contained the milkshake treat. The authors called this temptation-resistant voluntary exercise. They then injected mice with the pharmacological blocker of HON function to see how it impacted the choices mice made. If the milkshake was not in the maze, mice kept choosing exercise over all other options. When the milkshake was present, however, mice that received the blocker no longer chose exercise over milkshake, spending less time on the running wheel and more time eating. On the other hand, when the activity of HONs was increased using optogenetics, the mice spent even less time eating the milkshake.

Tesmer and colleagues then performed more experiments to understand exactly how HONs regulate this decision. Does HON activity make milkshakes inherently less appealing? No – when they blocked HON function in a maze with milkshake but no running wheel, the mice didn’t eat any extra milkshakes. Does HON activity make running inherently more appealing? No – when they blocked HON function in a maze with the wheel but no milkshake, the mice didn’t run any less. Instead, altering HON function only changed behaviour when BOTH the running wheel and milkshake were available as options – meaning that in a situation where mice are actively deciding between exercise and eating something highly palatable, HON activity leads to prioritizing exercise. The fiber photometry experiments support this notion: the activity of the HONs negatively correlated with milkshake eating, and positively correlated with wheel running.

What's the impact?

This study provides compelling evidence that HONs in the lateral hypothalamus play a role in the decision-making process between exercise and highly palatable foods. Of course, there is more work to do to determine if HONs play a similar role in human brains. This study takes a valuable step in understanding the neural foundations of such decisions, which can have important consequences for global health.  

Access the original scientific publication here.