Hippocampus and its involvement in Alzheimer’s disease:

 

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3 Biotech. 2022 Feb 1;12(2):55. doi: 10.1007/s13205-022-03123-4

Hippocampus and its involvement in Alzheimer’s disease: a review

Y Lakshmisha Rao 1, B Ganaraja 2, B V Murlimanju 

1,✉, Teresa Joy 3, Ashwin Krishnamurthy 4, Amit Agrawal 5

Abstract

Hippocampus is the significant component of the limbic lobe, which is further subdivided into the dentate gyrus and parts of Cornu Ammonis. It is the crucial region for learning and memory; its sub-regions aid in the generation of episodic memory. However, the hippocampus is one of the brain areas affected by Alzheimer’s (AD). In the early stages of AD, the hippocampus shows rapid loss of its tissue, which is associated with the functional disconnection with other parts of the brain. In the progression of AD, atrophy of medial temporal and hippocampal regions are the structural markers in magnetic resonance imaging (MRI). Lack of sirtuin (SIRT) expression in the hippocampal neurons will impair cognitive function, including recent memory and spatial learning. Proliferation, differentiation, and migrations are the steps involved in adult neurogenesis. The microglia in the hippocampal region are more immunologically active than the other regions of the brain. Intrinsic factors like hormones, glia, and vascular nourishment are instrumental in the neural stem cell (NSC) functions by maintaining the brain’s microenvironment. Along with the intrinsic factors, many extrinsic factors like dietary intake and physical activity may also influence the NSCs. Hence, pro-neurogenic lifestyle could delay neurodegeneration

Hippocampus and memory

The hippocampal sub-regions aid in the process of the generation of episodic memory (Langnes et al. 2020; Collin et al. 2015). 

The hippocampal-dependent memory signals 

outline memory formation, an active and ongoing process in the brain (Voss et al. 2017). According to de Landeta et al. (2020), the retrosplenial cortex in the occipital lobe plays a role in the long-term object recognition memory, similar to the hippocampus. The CA3 region of the hippocampus produces the sharp-wave ripples (SWR), which propagate the recent memory traces into the neocortex for consolidation of the memory (Karimi Abadchi et al. 2020). Supporting de Landeta et al. (2020) opinion, Karimi Abadchi et al. (2020) also found that the maximum SWR modulation occurs in the retrosplenial cortex. The excitatory output of SWR affects a larger area of the cortex along with the subcortical nuclei. This activity occurs during the ‘off-line’ state of the brain (Buzsáki 2015). The hippocampus proper is responsible for episodic memory (Knierim 2015). Samuel et al. (1994) observed that the neurofibrillary tangle (NFT) accumulation in the hippocampal region is related to dementia. The NFT accumulation in the stratum lacunosum, dentate fasciculus, CA2, CA3, and CA4 areas had resulted in the synaptic loss. During the early learning stage, the neocortical prefrontal engram cells are generated by the input from the hippocampus, entorhinal cortex, and basolateral amygdala. These prefrontal engram cells, with the aid of engram cells of the hippocampus, will eventually mature. Hence, the neocortical engram cells are a critical part of remote recollection (Kitamura et al. 2017; Roy et al. 2016). The oxidative damage can reduce the cognitive function in the cortex and hippocampus (Fonzo et al. 2009). The DG is one of the brain regions which shows neurogenesis throughout the life span of a mammalian. The DG, being an information gateway, has a significant contribution to the formation of episodic memory of the hippocampus (Poo et al. 2016; Eriksson et al. 1998; Altman and Das 1965).

Adult neurogenesis in hippocampus

Proliferation, differentiation, and migrations are the steps involved in adult neurogenesis. The sub-granular zone of DG and the sub-ventricular zone are the two regions consisting of neural stem cells (NSCs) of the adult brain, which show neurogenesis (Abbott and Nigussie 2020). The B1 cell residues, which line the junction between the stratum and lateral ventricle, possess the astroglial property and these cell residues act as the NSCs (Horgusluoglu et al. 2017). These NSCs, responsible for adult neurogenesis, are retained in the sub-ventricular and sub-granular zone regions of the DG in the adult brain. The olfactory bulb and DG are the two regions where neurogenesis is seen throughout life (Horgusluoglu et al. 2017). In the brain, neurogenesis occurs in a niche, where the NSCs are located near the blood vessels. Therefore, signals from the existing neural cells and nearby vasculature will stimulate the NSCs for neurogenesis (Ozek et al. 2018; Shen et al. 2008). Impairment in adult neurogenesis may be a critical factor for neurodegenerative disorders like AD and Parkinson’s disease. Genetic mutation, brain injury, and aging may cause depletion in the function of neural precursors (Shohayeb et al. 2018). The intrinsic factors like hormones, glia, and vascular nourishment will play a leading part in the role of NSCs by maintaining the microenvironment of the brain (Shohayeb et al. 2018; Licht and Keshet 2015).

Besides these intrinsic factors, few extrinsic factors like dietary intake and physical activity may also influence the NSCs. Hence it is understood that pro-neurogenic lifestyle could delay neurodegeneration. Neurotrophic factors (NTFs) can help the diseased neurons in AD and are offered through the viral vectors. The viral vectors can be inserted directly over that particular region, which has neuronal degeneration, and it will lead to the transduction of cells, which secrete the NTF. Besides this, stem cells may also help in neurodegenerative disorders like AD and Parkinson’s disease (Shohayeb et al. 2018).

Hippocampal lesions in AD

The neuropathological abnormality in AD includes neuronal loss and gliosis at the hippocampus (Ball et al. 1985). The volumes of hippocampal layers like stratum radiatum, stratum lacunosum, stratum moleculare and subiculum’s, stratum pyramidale are bilaterally lost in the patients of AD (Boutet et al. 2014). Though the etiology of AD is not clearly understood, the pathophysiology of AD demonstrates the neuro-inflammation, accumulation of Aβ peptides, phosphorylated tau, and oxidative stress (Reddy et al. 2017, 2012). The entorhinal area is the first region, where the plaques and tangles are deposited in AD patients (Knierim 2015). In the early stage of AD, tau protein gets accumulated in the entorhinal cortex and later spreads into the hippocampus (Asai et al. 2020). The anatomical and histological studies of autopsied AD brains have revealed that the neurodegeneration starts in the second layer of the entorhinal cortex and gradually extends into the hippocampus, temporal cortex, frontoparietal cortex and subcortical nuclei. In the later stages of the disease, there will be a disconnection between the DG and sub-regions of the hippocampus, leading to cognitive disorders (Reddy et al. 2018; Samuel et al. 1994; Hyman et al. 1986). Du et al. (2016) observed the accumulation of tau-1 positive foci in the polymorphic layer of the DG of rat models 7 days after the blast-induced traumatic cerebral injury. In AD, NFTs are first accumulated in the CA1 area of the hippocampus, then gradually affect the subiculum, CA2, CA3, and DG (de Flores et al. 2015; Lace et al. 2009). The tau positive neurons are associated with the Aβ deposits through their axonal projections in the AD brain. It was reported that Aβ deposition reduces the inputs in the hippocampus (Lace et al. 2009).