### Exploring Neuronal Subtype Vulnerability in Alzheimer’s
Alzheimer’s disease is a complex condition that affects the brain, causing memory loss and cognitive decline. One of the key aspects of Alzheimer’s is how different types of brain cells, called neurons, are affected. Some neurons are more vulnerable to the disease than others, and understanding this vulnerability is crucial for developing new treatments.
#### What Are Neurons?
Neurons are the building blocks of the brain. They help us think, remember, and move. There are many different types of neurons, each with unique roles. Some neurons are excitatory, meaning they help send signals to other neurons to make them more active. Others are inhibitory, meaning they help calm down or slow down the activity of other neurons.
#### Vulnerability in Alzheimer’s
In Alzheimer’s disease, some neurons are more likely to be damaged than others. This is known as selective vulnerability. Researchers have found that certain types of neurons, particularly those involved in memory and emotional processing, are more susceptible to the disease.
**Excitatory Neurons**
Excitatory neurons are those that help send signals to other neurons to make them more active. These neurons are crucial for memory and learning. In Alzheimer’s, excitatory neurons in the entorhinal cortex, a region important for memory, show unique resilience mechanisms. These mechanisms include the upregulation of certain proteins like Hsp40, Hsp70, and Hsp110, which help protect the neurons from damage. Specific markers like MEF2C, ATP8B1, and RELN are also identified as key markers of resilient excitatory neuronal populations[1].
**Inhibitory Neurons**
Inhibitory neurons, on the other hand, help calm down or slow down the activity of other neurons. These neurons are also affected in Alzheimer’s, but in different ways. Some inhibitory neurons, such as those expressing somatostatin (SST), are particularly vulnerable. These neurons play a crucial role in regulating the activity of excitatory pyramidal neurons. However, rare genetic variants can provide some protection to these neurons, making them less vulnerable to the disease[1].
**Mitochondrial Metabolism**
Inhibitory neurons, particularly those expressing parvalbumin (PV), have high energy consumption rates. This makes them more vulnerable to mitochondrial dysfunction, which is a hallmark of Alzheimer’s disease. Research has shown that impairments in mitochondrial bioenergetics in PV-interneurons are among the earliest abnormalities detected in both patients and animal models of AD[4].
**Amyloid Plaques and Tau Tangles**
Alzheimer’s disease is characterized by the accumulation of amyloid plaques and tau tangles in the brain. Amyloid plaques are clumps of beta-amyloid protein, while tau tangles are bundles of twisted filaments made of tau protein. These pathologic changes disrupt neural circuits and lead to neuronal loss, particularly affecting cholinergic neurons in the basal forebrain and cortex[3].
**Resilience Mechanisms**
Despite the vulnerability of certain neuronal subtypes, some individuals with Alzheimer’s pathology maintain healthy cognitive function. This phenomenon is known as cognitive resilience. Resilient brains protect cognition through a combination of synaptic plasticity, selective survival of SST+ inhibitory neurons, and an increase in their excitatory neuron populations. They also upregulate protein homeostasis, reduce neuroinflammation, and activate astrocytic responses to AD pathology[1].
Understanding the molecular and cellular mechanisms behind neuronal subtype vulnerability in Alzheimer’s is crucial for developing new treatments. By identifying the specific pathways and markers involved in resilience and vulnerability, researchers can develop targeted therapies to protect vulnerable neurons and preserve cognitive function.
In summary, Alzheimer’s disease affects different types of neurons in distinct ways. Excitatory neurons in the entorhinal cortex show unique resilience mechanisms, while inhibitory neurons, particularly those expressing SST, are more vulnerable. Mit
