Alzheimer's disease: A Double-Punch of Degeneration and Depletion in the Dentate Gyrus?

Could a shortage of dividing cells in the brain be a feature of Alzheimer’s disease? Recent research indicates this could be the case.

Your body is a mega-mash up of many different cell types working away at their specific jobs to keep you alive and kicking. Some of these cells are capable of dividing and producing near-identical daughter cells in a process called mitosis. For example, skin cells (aka keratinocytes) are able to divide to replace ‘old’ dead cells with fresh new ones - explaining why your summer tan fades after a few weeks of being back in grey weather (England y u like this?). Other cells in your body are not so keen on splitting apart into daughter cells and these are described as ‘post-mitotic’. Neurons, one of the major cells types of the brain, do not divide, meaning the key communicators of the central nervous system aren’t so easily replaced if they are lost. Conditions which cause the death of neurons, such as Alzheimer’s disease, are normally irreversible and notoriously difficult to treat.

New year, New Neurons: Neurogenesis in the Adult Brain

Although neurons are post-mitotic, there are two known pools of neural stem cells in the adult brain. Neural stem cells can divide and produce the precursor cells which are able to mature into specific neurons throughout life. One of these pools is found in the subventricular zone of the lateral ventricle (a lahttt of words to describe a region near one of the fluid-filled holes in your brain), which is believed to give rise to inhibitory interneurons of the olfactory bulb (your 'smell' region). The other pool is in the dentate gyrus, which forms part of the hippocampal formation; the brain region vital for generating long-term memories. The pool of neural stem cells in this region mature through several stages to become excitable dentate granular cells (DGCs).

DGCs are morphologically beaut neurons, having a small cell body from which a web of neuronal processes project. Their extensive branch-like dendrites can receive thousands of excitatory signals from the entorhinal cortex, a brain region proposed to integrate mounds of 'higher function' information (sensory, motor, spatial and language inputs to name a few) received in your neocortex. The DGCs process these inputs and transmit their own excitatory signals along their mossy-fibre axonal projections to the CA3 region of the hippocampus. Immature DGCs, produced during neurogenesis, are believed to be super important for learning and memory functions as they are extremely excitable, sending signals with little stimulation, and are plastic, easily altering the strength of their synaptic connections. Once DGCs become mature, they become less eager to signal to the CA3 neurons and find it more difficult to alter their synaptic strength, but when they do signal, these are believed to be in robust 'bursts'; making sure the CA3 neurons really get their message. In terms of functionality, evidence suggests DGCs at both immature and mature stages play vital roles in memory formation.

Out with the Old, No Cells for the New: Alzheimer’s disease and Neurogenesis

So whasoccurin' with these DGCs in conditions of permanent memory loss? In a recent paper published in Nature Memory, Moreno-Jimenéz et al describe the loss of numbers and lack of maturation of DGCs and their progenitors in patients with Alzheimer’s disease (AD). AD is a common, age-related neurodegenerative condition and one of the initial subsets neurons to die in a patient's brain are in the hippocampus; resulting in the progressive loss of memory. Specifically, 'ground zero' of Alzheimer's disease, describing the region first affected by neurodegeneration, is believed to be the entorhinal cortex. Therefore, DGCs in the dentate gyrus are left with reduced stimulation from entorhinal projections and eventually succumb to neurodegeneration themselves, meaning the ability to convert novel experiences into long-term memory is majorly disrupted. However, the effect Alzheimer’s disease has on the pool of neural stem cells and progenitors in this region in humans has only recently been investigated.

Moreno-Jimenéz and colleagues present data using human brain fixed tissue investigating how neural stem cells and progenitors in the dentate gyrus are affected by age and AD. The researchers revealed individuals with normal cognition have an abundant pool of neural stem cells and high numbers of neural precursors in the dentate gyrus until over 80 years of age, with age moderately reducing these numbers over time. However, in individuals with Alzheimer’s, these pools were significantly depleted irrespective of patient age. The root of this depletion was described by the lack of neural progenitor maturation with AD progression, as the numbers of immature DGCs were significantly reduced in AD brain slices. These findings suggest AD has an abnormal effect on neural stem and progenitor cells numbers which are not concurrent with normal age-related changes, and this is potentially due to problems with maturation of progenitors in the dentate gyrus.

What does this mean for disease-associated mechanisms related to AD? It is already established that AD somehow drives the death of dentate granule cells alongside other neurons in the hippocampus, but if the disease also prevents the production of replacement cells, this creates a double inhibitory effect. Maintaining the number of neural precursors and driving their maturation in AD patients may delay or prevent the onset of memory deficits in AD as these cells could replace those lost to the disease. However, it still unclear how having an abundance of healthy neural precursors in a potentially neurotoxic environment would aid patients in the long run. It will be important to establish whether AD causes or is caused by changes to DGCs maturation, which will require us to answer the big question: what causes neurons to die in AD? And unfortunately, that is still a complete mystery. But what this work shows is that there may be more to AD that just hippocampal cell death. In fact, it suggests AD could be a double hit of mature neuronal death and new neuron production disruption. Further research into the dynamics and origins of these two mechanisms could open up an interesting avenue on the road to AD therapeutics.

Main Paper: Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease, Moreno-Jimenéz et al (2019)

Other References used for your further reading pleaaaaasures

Neurogenesis in Adult Subventricular Zone

Adult neural stem cells in the mammalian central nervous system

Entorhinal Cortex

Mature granule cells of the dentate gyrus: passive bystanders or principal performers in hippocampal function?

Neural stem/progenitor cells in Alzheimer’s disease

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