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Abstract

The hippocampus is a significant component of the limbic lobe, comprising subdivisions such as the dentate gyrus (DG) and various parts of the Cornu Ammonis (CA). It is essential for learning and memory, particularly in relation to the generation of episodic memory—memories of personal experiences and specific events. Alzheimer’s disease (AD) severely impacts the hippocampus, especially in its early stages, with rapid tissue loss leading to functional disconnection from other brain regions. Neuroimaging techniques, notably Magnetic Resonance Imaging (MRI), reveal progressive atrophy in medial temporal regions and hippocampal areas, which are critical for memory processes.

A lack of sirtuin (SIRT) expression in hippocampal neurons has been shown to be detrimental to cognitive functions, including recent memory recall and spatial learning capabilities. Adult neurogenesis, which involves the processes of neural stem cell proliferation, differentiation, and migration, is significantly affected in AD. Moreover, microglial activity within the hippocampal region is notably heightened compared to other brain areas, indicating an altered immune response. Both intrinsic (hormones, glia, vascular support) and extrinsic factors (diet, physical activity) influence neural stem cell (NSC) functions, suggesting that adopting a pro-neurogenic lifestyle may delay the progress of neurodegeneration, particularly in diseases like AD.

Introduction

The cerebral cortex and hippocampus are interconnected, playing vital roles in cognitive functions and neurogenesis, as noted in studies by Hu et al. (2019). In addition to β-amyloid and tau proteins, the TAR DNA-binding protein of 43 kDa (TDP-43) has recently been associated with AD pathogenesis. The accumulation of TDP-43 in the amygdala, which spreads into the hippocampus, is linked to accelerated atrophy and cognitive decline, highlighting the need for therapeutic strategies that can prevent TDP-43 spread (Josephs et al. 2017). Furthermore, genetic neuroimaging studies indicate that risk alleles for AD significantly affect cortical and hippocampal morphometry (Lancaster et al. 2019), underscoring the importance of genomic contributions to disease risk.

Neuronal degeneration in AD correlates with the abnormal accumulation of proteins such as β-amyloid and tau, leading to either excessive formation or reduced clearance of amyloid-beta (Aβ). Pathologically, AD is characterized by the extracellular accumulation of senile plaques and the formation of intracellular neurofibrillary tangles, both of which have significant incidences in the hippocampus (Chu 2012). This degeneration is a prominent aspect contributing to cognitive decline often observed in aging as well as in disorders such as AD (Jaroudi et al. 2017). It is noteworthy that while hippocampal degeneration can occur in other neurodegenerative diseases (like Lewy body dementia), the degree of atrophy observed in AD is markedly more pronounced. A deeper understanding of hippocampal variations can lead to improved diagnostic measures and treatment options for AD (Elder et al. 2017).

Subdivisions of Hippocampus and the Papez Circuit

The hippocampus consists of several subdivisions, with the dentate gyrus (DG) and multiple components of cornu ammonis (CA1, CA2, CA3, CA4) demonstrating distinct cellular architectures. The DG is characterized by tightly packed granule cells oriented toward the hippocampal fissure, contributing to its role in processing new memories and facilitating learning (Mufson et al. 2015). The CA regions predominantly contain pyramidal cells, which are crucial for the integrated processing of memory-related information.

Papez (1937) described a circuit connecting the cingulate gyrus with the hippocampus through the mammillary bodies and anterior thalamus, known as the Papez circuit. This neural circuit is essential for mnemonic functions, particularly short-term spatial memory, and various cognitive processes (Brennan et al. 2019). Disruptions within this circuit can lead to deficiencies in episodic memory and learning.

Microanatomy of the Hippocampus

Structurally, the hippocampus is classified as a trilaminate archicortex, and it features upper and lower plexiform layers that sandwich a pyramidal cell layer. The distinct CA fields (CA1, CA2, CA3, CA4) are defined by their cellular arrangements and functions (Brennan et al. 2019). The CA3 field, for instance, receives significant input via mossy fibers from the DG, while CA2 is known for its densely packed pyramidal cells that predominantly receive inputs from the hypothalamus. A unique overlap exists between CA1 and the subiculum, containing approximately 10% of interneurons critical for modulating the excitatory activity of pyramidal neurons. Neurogenesis, predominantly occurring in the sub-granular layer of the DG, is essential for functions like learning and long-term memory retention (Poo et al. 2016).

Blood Supply of the Hippocampus

The arterial supply of the hippocampus is primarily derived from branches of the posterior cerebral artery, a branch of the basilar artery, and the anterior choroidal artery, which originates from the internal carotid artery. It is important to note that the vascular supply can vary among individuals (Spallazzi et al. 2019). Specifically, the anterior hippocampal artery serves the head and uncut regions, the middle hippocampal artery supplies the body, and the posterior hippocampal artery extends toward the tail. Recognizing these blood supply variations is crucial for surgical interventions involving the hippocampal area, as well as for understanding potential vulnerabilities related to ischemia.

Connections of the Hippocampus

The significant afferent connections to the hippocampus originate from the entorhinal cortex via the perforant path and through the fimbria/fornix, linked with inputs from the basal forebrain and brainstem. The hippocampus plays a vital role in facilitating episodic memory formation, with CA2 and CA3 regions receiving extensive inputs that are critical for encoding and retrieval processes (Lisman et al. 2017). However, disruptions to the perforant pathway have been shown to result in cognitive impairments, underlining its importance in maintaining healthy cognitive functions (Ginsberg 2010).

The Role of the Hippocampus in Memory

The hippocampus is central to generating episodic memory, with its sub-regions supporting various ongoing memory formation processes (Langnes et al. 2020; Collin et al. 2015). The CA3 region produces sharp-wave ripples (SWR), which play a fundamental role in propagating recent memory traces into the neocortex for consolidation (Karimi Abadchi et al. 2020). During the early phases of learning, engram cells—generated from hippocampal input—culminate in the activation and maturation of prefrontal engram cells, which are critical for remote recollection (Kitamura et al. 2017; Roy et al. 2016). The presence of oxidative stress can significantly hinder cognitive functions within both the cortex and hippocampus, affecting overall memory performance (Fonzo et al. 2009).

The DG region exhibits a unique capacity for neurogenesis throughout adulthood, functioning as a critical gateway for episodic memory formation—this is underscored by the presence of new neurons that are integrated into existing neuronal circuits, enhancing memory processing capabilities (Poo et al. 2016; Eriksson et al. 1998; Altman and Das 1965).

Adult Neurogenesis in the Hippocampus

The biological processes of adult neurogenesis encompass neuronal proliferation, differentiation, and subsequent migration of newly formed neurons. The sub-granular zone of the DG, along with the sub-ventricular zone, harbors neural stem cells (NSCs) responsible for maintaining neurogenesis within the hippocampus (Abbott and Nigussie 2020). Importantly, B1 cell residues present at the junction of the stratum and lateral ventricle act as NSCs, contributing to ongoing neurogenesis (Horgusluoglu et al. 2017). The niche environments surrounding blood vessels significantly influence neurogenesis, as growth factors and signals can stimulate NSCs (Ozek et al. 2018).

Impairment of neurogenesis serves as a significant marker for neurodegenerative disorders such as AD and Parkinson's disease, with contributing factors including genetic mutations and the natural aging process (Shohayeb et al. 2018). Intrinsic factors like hormones, supportive glial cells, and adequate vascular nourishment are critical for optimal NSC functions and healthy neural environment (Shohayeb et al. 2018; Licht and Keshet 2015). Additionally, extrinsic factors, including dietary habits and levels of physical activity, profoundly influence neurogenesis; adopting a pro-neurogenic lifestyle has been suggested to mitigate neurodegenerative progression. Notably, neurogenic factors (NTFs), when administered via neural vectors, can support diseased neurons in AD, promoting cellular transduction and enhancing neuroprotection (Shohayeb et al. 2018).

Hippocampal Lesions in AD

Neuropathological abnormalities associated with AD encompass significant neuronal loss and gliosis within the hippocampus (Ball et al. 1985). Patients with AD typically experience volume loss across various hippocampal layers, including stratum radiatum and stratum lacunosum (Boutet et al. 2014). While the exact etiology of AD remains unclear, pathophysiological insights reveal neuroinflammation driven by Aβ peptides, phosphorylated tau, and oxidative stress as core contributors to disease progression (Reddy et al. 2017, 2012). Furthermore, the entorhinal area is usually the initial site of plaque and tangle deposition, demonstrating the dynamic nature of pathology across brain regions (Knierim 2015). Tau protein accumulates in the entorhinal cortex before spreading into hippocampal regions, further complicating the disease's impact on cognitive function (Asai et al. 2020). As AD progresses, disconnections among the DG and various hippocampal sub-regions lead to pronounced cognitive disorders in later stages (Reddy et al. 2018; Samuel et al. 1994; Hyman et al. 1986).

Microglial Activity in AD

Microglia, the brain's resident immune cells, play multifaceted roles in the development of the central nervous system, including neurogenesis and axonal growth, which adapt during hippocampal maturation (Delpech et al. 2016; Parkhurst et al. 2013). Elevated microglial activity, particularly in the hippocampus, is essential for refining synaptic connections and facilitating the clearance of Aβ plaques, which are hallmarks of AD (Rivera-Escalera et al. 2019). Activation of microglia usually occurs at the onset of AD, characterized by increased inflammatory markers in cerebrospinal fluid, where pro-inflammatory cytokines can trigger both microglial proliferation and the promotion of Aβ removal via phagocytosis (Sarlus and Heneka 2017).

Growth Factors in the Hippocampus

Neurotrophins—such as nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), and brain-derived neurotrophic factor (BDNF)—play a vital role in enhancing neuron survival in patients with AD (Hock et al. 2000). BDNF, in particular, is crucial for neuron maintenance across various insults affecting brain regions, including the hippocampus (Rai et al. 2013). Studies have indicated that there is a notable decline in BDNF levels correlating with neuronal degeneration in AD (Hock et al. 2000), while NGF levels may increase in response to neuronal loss, suggesting potential targets for therapeutic interventions.

Impact of Hormones on Hippocampal Function

Glucocorticoid hormones, which are secreted during stress, significantly influence cognitive functions within the hippocampus. Chronic exposure to high levels of glucocorticoids can lead to detrimental effects on both hippocampal structure and cognitive abilities in AD patients (Libro et al. 2017). Evidence suggests that elevated endogenous glucocorticoids can exacerbate Aβ deposition in AD models, further impacting overall cognitive health (Libro et al. 2017). Additionally, fluctuations in sex hormone levels, specifically ovarian hormones and testosterone, have been shown to influence hippocampal neuronal proliferation; elevated ovarian hormone levels can enhance neurogenesis, whereas decreased testosterone levels can hinder this process (Shohayeb et al. 2018).

Proneurogenic Lifestyle and Neurodegeneration

The impact of lifestyle choices—such as exercise and diet—on hippocampal function and overall neurogenesis is substantial. Research conducted on animal models demonstrates that physical activities like running can promote neurogenesis within the hippocampus. Conversely, chronic stress and diets high in fat have been shown to impair neuroprogenitor cell proliferation and increase apoptotic processes in the DG (Park et al. 2011). Therefore, recognizing the significance of maintaining healthy dietary and lifestyle choices is critical for mitigating neurodegeneration and promoting cognitive health throughout life.

Conclusion

The severe neuronal loss and gliosis evident in the hippocampus highlight critical aspects of AD pathology, where advanced shrinkage often correlates with deficits in short-term memory. Microglia that initially contribute positively by removing Aβ can become detrimental in later stages of AD due to chronic inflammation. A comprehensive understanding of microglial functions, growth factors, and the environmental influences on neurogenesis can greatly enhance management and treatment strategies for AD. Emphasizing balanced lifestyle choices, hormonal health, and external factors regulating hippocampal neurogenesis is essential in fostering long-term cognitive wellness and mitigating the progression of neurodegenerative diseases.