Neurogenesis in the Adult Brain: Implications for Alzheimer's Disease Pathology and Treatment

ABSTRACT

Adult neurogenesis, once believed to be restricted to early development, has been shown to occur in brain regions such as the hippocampus, where it contributes to cognitive functions such as learning and memory. More specifically, it occurs in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. In the SGZ of the DG within the hippocampus, neural stem cells (NSCs) are generated, which develop in stages of intermediate progenitor cells, proliferating neuroblasts, immature neurons, and finally, mature granule cells. While current understandings of neurogenesis function is not completely clear, many studies demonstrate that neurons can be functionally integrated into the hippocampus, thus resulting in the belief that ABNs contribute to learning and memory. This review hence explores neurogenesis’ potential link to Alzheimer’s disease (AD), a leading cause of dementia characterized by cognitive decline, which has been known to affect the hippocampus first. Evidence from human studies and animal models suggests that impaired neurogenesis may be associated with AD. However, inconsistencies in findings and the limitations of animal research highlight the need for further investigation, as the data cannot be directly applied to humans. Moreover, understanding the role of neurogenesis in AD could inform new therapeutic approaches for this currently incurable disease. Currently, research is being done to explore this potential, primarily through genetic and pharmacological stimulation of adult hippocampal neurogenesis (AHN). Through this technique, scientists hope to better understand the relationship between AHN and overall cognitive function.

Introduction

Neurogenesis, the process of generating new neurons from neural stem cells, has long been a focal point in neuroscience, especially regarding its implications for brain function and disease. Initially believed to occur only during prenatal development and early postnatal life, neurogenesis was thought to cease in adulthood. (Kim et al., 2022) However, research in the latter half of the 20th century challenged this notion, revealing that neurogenesis does continue in certain regions of the adult brain, particularly the hippocampus. (Altman & Das, 1965) The discovery of adult neurogenesis has led to a deeper exploration of its role in various neurological functions, including learning, memory, and cognitive resilience.

Alzheimer's Disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline, memory loss, and behavioral changes. (Scheltens et al., 2021) As the leading cause of dementia, AD affects millions of people worldwide, with a significant impact on individuals and society. The hippocampus, a critical region for memory and learning, is one of the first areas affected by AD. Given the hippocampus's role in adult neurogenesis, researchers have been investigating the relationship between neurogenesis and AD, seeking to understand how impairments in this process may contribute to the progression of the disease. Considering the massive impact AD has on millions of individuals worldwide, the overall purpose of this review is to highlight the relationship between adult neurogenesis and AD in order to explore the potential therapies that may arise from it.

Exploring Adult Neurogenesis: History, Development, and Function

History

Neurogenesis, the process of generating new functional neurons from neural stem cells, was long accepted to be limited to prenatal development and early postnatal life in mammals. (Kim et al., 2022; Rodríguez & Verkhratsky, 2011) This belief stemmed from Santiago Ramón y Cajal’s “no new neurons” theory in 1913, in which he believed neurogenesis ceased in the adult brain, which served as a fundamental principle in neuroscience for decades. (Rodríguez & Verkhratsky, 2011) In the 1960s, however, Joseph Altman kickstarted the beginning of a major reconsideration of Cajal’s long-standing doctrine; through 3H-thymidine labeling, Altman presented newborn neurons in an adult rat hippocampus, providing the field’s first anatomical evidence of adult neurogenesis. (Altman & Das, 1965; Kim et al., 2022; Ming & Song, 2011) By 1977, Kaplan and Hinds confirmed Altman’s previous observations through similar findings in the rat hippocampus and olfactory bulb. (Kaplan & Hinds, 1977) It was not until Paton and Nottebohm’s work with songbirds in 1984 that evidence of new neurons being successfully functionally integrated into an existing neural network came to light.6 Paton and Nottebohm found that adult songbirds generated new neurons as they learned a song, which aided the birds in memorization and impacted their cognitive function. (Paton & Nottebohm, 1984) This study, hence, marks a significant turning point in the credibility and recognition of adult neurogenesis in neuroscience. Numerous studies have since been performed, and with the help of various technological advancements, such as bromodeoxyuridine (BrdU) as well as genetic and viral labeling, the phenomenon of adult neurogenesis is now widely acknowledged. (Kim et al., 2022)

Region and Development

Adult neurogenesis is spatially restricted to occur in only two regions of the brain: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. (Ming & Song, 2011; Rodríguez & Verkhratsky, 2011) The SVZ and SGZ, also known as the neurogenic niches, contain the multipotent neural stem cells (NSCs) necessary for adult hippocampal neurogenesis (AHN). (Cope & Gould, 2019; Kim et al., 2022; Rodríguez & Verkhratsky, 2011)

In the SGZ, several thousand new hippocampal dentate granule cells are generated daily in the DG. (Ming & Song, 2011; Rodríguez & Verkhratsky, 2011) Neural stem cells give rise to intermediate progenitor cells, which in turn generate proliferating neuroblasts, immature neurons (~2-4 weeks), and eventually mature granule cells (~6-8 weeks) within their place in the DG granule cell layer.1,2 Most newborn neurons in the hippocampus die within a one to three-week span. (Tashiro et al., 2006) In the SVZ, on the other hand, the new neurons generated move through the rostral migratory stream (RMS) towards the olfactory bulb, where they develop into local interneurons. (Kim et al., 2022; Ming & Song, 2011; Rodríguez & Verkhratsky, 2011)

Function

The hippocampus, a brain region heavily involved in learning and memory, is connected via a trisynaptic loop composed of the DG, cornu ammonis (CA) 1, and CA3. (Borzello et al., 2023; Kim et al., 2022) The SGZ of the DG, as previously discussed, is one of the neurogenic niches in the brain responsible for adult neurogenesis. These adult-born neurons (ABNs) can be functionally integrated into the hippocampal circuitry, posing supporting evidence for scientists to believe ABNs take part in crucial hippocampal functions such as learning and memory. (Dieni et al., 2019; Miller & Sahay, 2019; Toda et al., 2019)

Although the exact function of ABNs is not yet completely understood, many studies utilize pharmacological, chemogenetic, optogenetic, or irradiation methods to forcibly induce a reduction of neurogenesis in rodents in order to assess its effects on brain function. (Hersman et al., 2016; Kim et al., 2022) The general trend of such studies showcased impaired ability in tasks relevant to pattern separation, forgetting, learning, and memory. (Clelland et al., 2009; Gao et al., 2018; Garthe et al., 2009; Miller & Sahay, 2019) However, some other labs have found no effect or even slightly improved ability on functions such as spatial pattern separation as a result of a loss of ABNs. (Creer et al., 2010) These discrepancies in data may stem from varying methods in ABN depletion or off-target effects from certain techniques, as it is difficult to reduce neurogenesis without any residual effect on its surroundings. (Kim et al., 2022; Toda et al., 2019) However, it is generally accepted that ABNs play a role in learning and memory due to their functional integration into the DG of the hippocampus. (Toda et al., 2019)

Overview of Alzheimer’s Disease

History and Clinical Overview

AD, the main cause of dementia, is a disorder that causes a deterioration in memory, thinking, and behavior. (Scheltens et al., 2021) AD accounts for up to 80% of all dementia cases and currently affects over 55 million people worldwide. (Gustavsson et al., 2023; Weller & Budson, 2018) The disease typically affects the hippocampus first, a brain region responsible for learning and memory; hence, the loss of cognitive function is a telltale sign of AD. German psychiatrist Alois Alzheimer, after whom the disease is named, was the first to notice a significant amount of amyloid plaques and neuron loss in the cerebral cortex of his patient, who experienced severe memory loss and personality change prior to death. (Breijyeh & Karaman, 2020) It is from Alzheimer’s initial discovery and description of the condition that the field of AD emerged.

Possible Causes and Influential Risk Factors

Although the exact cause of AD still remains unknown, the two most common hypotheses for AD pathogenesis include the cholinergic hypothesis and the amyloid hypothesis. (Breijyeh & Karaman, 2020; Kim et al., 2022) Acetylcholine (ACh) is a neurotransmitter in the brain that plays a pivotal role in various tasks such as memory, learning, attention, and sensory information. (Brown, 2019) The cholinergic hypothesis, one of AD pathogenesis’ earliest theories, arose from the discovery of the degeneration of cholinergic neurons as well as the inhibition of choline uptake and ACh release in AD patients. (Breijyeh & Karaman, 2020; Kim et al., 2022) The amyloid hypothesis, on the other hand, explores the accumulation of β-amyloid peptides and their subsequent role in neurotoxicity and the initiation of tau pathology. (Breijyeh & Karaman, 2020; Chen et al., 2017; Kim et al., 2022; Scheltens et al., 2021) Tau is a protein that forms insoluble filaments that accumulate in the brain as neurofibrillary tangles, contributing to AD progression. (Medeiros et al., 2010) β-amyloid is a sticky compound formed from the amyloid precursor. This larger membrane protein can build up in the brain over time and disrupt brain cell signaling. (Chen et al., 2017; Conti & Cattaneo, 2005) The amyloid hypothesis is currently considered the most widely accepted hypothesis for AD pathogenesis. (Breijyeh & Karaman, 2020)

Several risk factors for AD include age, genetics, environment, and other medical conditions. (Kim et al., 2022; Scheltens et al., 2021) Age, however, proves to be the strongest risk factor for AD by far; the vast majority of AD patients are over 65 years old, as the disease is extremely rare in young individuals. (Breijyeh & Karaman, 2020) Additionally, studies show that the development of AD is 60-80% related to genetics and heritable factors. (Breijyeh & Karaman, 2020; Scheltens et al., 2021) AD is associated with certain mutations in dominant genes such as amyloid precursor protein (APP), presenilin-1 (PSEN-1), presenilin-2 (PSEN-2), and apolipoprotein E (ApoE). (Breijyeh & Karaman, 2020)

Adult Neurogenesis in Alzheimer’s Disease

In order to understand the relationship between AHN and AD, substantial work has been conducted using animal models. Since AD is unique to the human species and can only be partially replicated in animal models, scientists often turn to post-mortem brain samples from individuals with AD to gain more comprehensive insights. (Rodríguez & Verkhratsky, 2011; Toledano & Alvarez, n.d.)

Impaired Neurogenesis in AD Rodent Models

Researchers rely not only on human studies but also on rodent models to assess the relationship between neurogenesis and AD. A recent study examined the role of the APP intracellular domain (AICD), a result of processing APP, in neurogenesis in mice and found that AICD decreased the neural progenitor cell (NPC) pool, increased cell death, and impeded the proliferation and differentiation efficiency of NPCs. (Jiang et al., 2020; Li et al., 2015) Using a forced swim test and tail suspension test, they also found a depression-like behavioral phenotype in the AICD transgenic mice. (Jiang et al., 2020) This ultimately demonstrates the effects of an overexpression of AICD and its relationship with neurogenesis in mice.

Moreover, Rodriguez et al. explored transgenic mice (3xTg-AD) with three mutant genes (β-amyloid precursor protein, presenilin-1, and tau) at 2, 3, 4, 6, 9, and 12 months old in comparison to non-TG controls. (Rodríguez et al., 2008) They found that the reduction of neurogenesis in the 3xTg-AD mice was directly correlated to the presence of β-amyloid plaques in the hippocampus, suggesting impaired neurogenesis in the DG of the hippocampus, which is associated with Alzheimer's disease and age-related changes. (Rodríguez et al., 2008) Although working with animal models serves as a valuable alternative to the limitations of human studies, the data observed cannot be completely extrapolated to humans. This is partly due to the struggle to design accurate cognition tests and species variability. However, these studies still play a crucial role in expanding our understanding of certain topics in order to conduct future research.

Impaired Neurogenesis in AD Human Patients

In 2019, Moreno-Jiménez et al. found thousands of doublecortin (DCX+)-expressing neurons in the DGs of healthy, post-mortem brain tissues. (Moreno-Jiménez et al., 2019) In order to ensure optimal results, the samples were cautiously selected under tightly controlled conditions in which the researchers evaluated factors such as previous medical records and post-mortem delay. (Moreno-Jiménez et al., 2019) During the immunohistological analysis of AD brains, however, they found a dramatically reduced number of DCX+ immature neurons. (Moreno-Jiménez et al., 2019) Similarly, Tobin et al. found that while AHN does continue with aging, the DCX+PCNA+ cells were still reduced in patients with mild cognitive impairments and AD. (Tobin et al., 2019) Then, in 2022, Zhou et al. utilized single-nucleus RNA sequencing (snRNA-seq) to find that AD patients had a twofold lower percentage of DCX+Prox1+Calbindin cells compared to the controls. (Zhou et al., 2022) Moreover, 14 genes related to signaling and synaptic plasticity were downregulated in the immature dentate granule cells in AD patients. (Zhou et al., 2022)

However, some earlier studies bring to light a few discrepancies in the notion that AD yields earlier and faster AHN decline. In 2003, one instance occurred in which Jin et al. reported an increase in DCX, TUC4, and PSA-NCAM in the SGZ of the DG, the granule cell layer, and the CA1 region of Ammon’s horn, hence suggesting an increase in AHN in AD patients. (Jin et al., 2004) Due to inconsistencies in data such as this, further work still needs to be done regarding the relationship between AHN and AD.

Therapeutic Potential of ABNs in AD

Studies have been conducted to explore the therapeutic potential of ABNs in AD patients through, for instance, genetic and pharmacological stimulation of AHN. Choi et al. performed one such experiment in AD transgenic 5xFAD mice, which allowed them to examine the effect of increasing AHN on AD pathology and symptoms. (Choi et al., 2018) Although AHN alone yielded minimal to no improvement in cognition, exercise-induced AHN did show improved cognition, a reduced amyloid β load, and a spike in brain-derived neurotrophic factor (BDNF) levels. (Choi et al., 2018) They were also able to mimic these results from exercise through genetic and pharmacological AHN stimulation in combination with increasing BDNF levels. (Choi et al., 2018) Moreover, suppressing AHN in the early stages of AD resulted in neuronal vulnerability later on, which led to impaired cognition and an uptick in neuronal loss. (Choi et al., 2018)

Another recent study by Walgrave et al. discussed the relationship between AHN stimulation and improved cognitive function in mice. Initially, they discovered that a microRNA downregulated in AD, known as miR-132, positively regulates AHN in both mice and human NSCs. (Mishra et al., 2022) By overexpressing miR-132 in mice and reinstating AHN, the AppNL-G-F mice demonstrated restored memory deficits in pattern separation and passive avoidance testing. (Mishra et al., 2022) This study consequently exhibits a potential for reverse cognitive impairment in AD patients through AHN stimulation. Ultimately, although there is yet to be a concrete cure for AD, these studies provide potential therapeutic approaches to improving cognition and preventing or delaying cognitive impairment in AD patients.

Methods

PubMed, Google Scholar, and the UC Irvine Library databases were searched using keywords such as adult neurogenesis, Alzheimer’s disease, hippocampus, and cognitive function. Papers were eligible for selection based on whether or not they are peer-reviewed, published literature in the English language, as well as their relevance to the role of neurogenesis in Alzheimer’s disease.

Conclusion

This review discussed the history, development, and function of neurogenesis, an overview of Alzheimer’s disease, previous human and animal studies of neurogenesis in AD, and the current therapeutic applications of this field. Throughout this analysis, the correlation between impaired neurogenesis and AD was revealed. The significance of these findings comes from an enhanced understanding of the process behind AD, yielding the potential to develop new therapeutic approaches to AD—a disease with no current cure. However, some of the studies examined were limited by inconsistent methodology, varying samples, and the use of rodent models, which cannot fully translate to human conditions. Therefore, it is essential to approach each study with a degree of caution. In the future, it may be possible to develop a working form of therapy for AD. However, further research is necessary to solidify the connection between AHN and AD.

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