The hippocampus plays a crucial role in memory formation, spatial navigation, and cognitive function, making it one of the earliest and most severely affected regions in Alzheimer’s disease (AD). AD is driven by the accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs), leading to synaptic dysfunction, neuroinflammation, and progressive neuronal loss. This review explores age-related cellular changes in the hippocampus using findings from single-cell RNA sequencing (scRNA-seq), transcriptomics, and AD mouse models.
Recent studies have demonstrated that 81% of human protein-coding genes are expressed in the hippocampus, with 45 genes exhibiting regional elevation. Genes such as NECAB1, CALB2, GRIA1, NRGN, and ICAM5 are highly expressed across species and play critical roles in synaptic signaling and neurotransmission. However, these genes become dysregulated in AD, contributing to early cognitive decline.
Age-related changes in hippocampal cell populations include early synaptic loss in neurons, hyperactivation of microglia, reactive astrogliosis, and declining neurogenesis in the dentate gyrus. Pro-inflammatory microglial clusters, enriched in Trem2, Il1β, Ccl3, and Lpl, promote chronic neuroinflammation, impair Aβ clearance, and exacerbate neuronal damage. Tau pathology is particularly severe in the CA1 region, where hyperphosphorylated tau spreads via synaptic circuits, disrupting hippocampal connectivity.
Findings from AD mouse models (APP/PS1, 5xFAD, P301S Tau) show that these age-related changes emerge as early as 3–6 months, with progressive neuroinflammation and synaptic degeneration. Insights from multi-omics datasets and AI-driven analysis suggest that targeting microglial activation, synaptic dysfunction, and neurogenesis may offer novel therapeutic strategies. TREM2 agonists, CSF1R inhibitors, IL-1β blockers, and gene therapy approaches hold promise in restoring hippocampal function and slowing AD progression.
This review highlights the importance of cell-type-specific transcriptomics and spatial profiling in uncovering the molecular underpinnings of hippocampal vulnerability in AD. Future research should focus on early intervention strategies, integrating single-cell and spatial omics technologies to develop precision medicine approaches targeting hippocampal dysfunction in neurodegenerative diseases.
Introduction
The hippampal formation is a crucial brain structure responsible for memory formation, spatial navigation, and cognitive function. It consists of several anatomical subdivisions, including the hippocampus proper (CA1–CA3), dentate gyrus, subiculum, and surrounding cortical areas.
Located in the temporal lobe, the hippocampus is among the earliest and most severely affected brain regions in Alzheimer’s disease (AD). AD is driven by the accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs), which cause synaptic dysfunction, neuroinflammation, and neuronal loss.
Gene Expression in the Hippocampus
Recent transcriptome studies have shown that:
81% of human protein-coding genes are expressed in the hippocampus, with 45 genes exhibiting regional elevation (Fani et al., 2022).
63% of mouse genes (91 elevated genes) and 71% of pig genes (121 elevated genes) are expressed in the hippocampal formation.
32 genes show enrichment across species, with five genes (NECAB1, CALB2, GRIA1, NRGN, ICAM5) being highly expressed in humans, mice, and pigs.
Proteins such as NECAB1, CALB2, and GRIA1 are essential for synaptic signaling and neurotransmission, which are crucial for hippocampal function. Their dysregulation in AD contributes to cognitive deficits.
Hippocampal Vulnerability in AD
Aβ plaques disrupt synaptic signaling, triggering inflammation and neurotoxicity.
Tau pathology, marked by hyperphosphorylation of tau proteins, leads to neurofibrillary tangles that impair microtubule function and neuronal transport.
The CA1 region of the hippocampus is particularly vulnerable to tau-mediated degeneration, contributing to early memory impairment in AD patients (Braak & Del Tredici, 2020).
Latest Research on the Hippocampal Role in AD
1. Synaptic Dysfunction and Memory Impairment
Single-cell RNA sequencing (scRNA-seq) has identified hippocampal neuronal subpopulations vulnerable to AD, showing early synaptic loss and excitotoxicity (Leng et al., 2021).
NRGN (Neurogranin), a hippocampal-specific protein involved in synaptic plasticity, is significantly reduced in AD patients, contributing to cognitive deficits (Kvartsberg et al., 2019).
2. Tau Pathology and CA1 Vulnerability
Hyperphosphorylated tau spreads through hippocampal circuits via synaptic connections, with the entorhinal cortex and CA1 being the earliest affected regions (Braak & Del Tredici, 2020).
Neuroinflammation exacerbates tau pathology, as astrocytes and microglia release pro-inflammatory cytokines, promoting tau aggregation and neuronal loss (Henstridge et al., 2019).
3. Amyloid-Beta and Glial Interactions
Aβ accumulation in the hippocampus activates microglia, leading to chronic inflammation and neuronal death (Leng & Edison, 2021).
The ICAM5 gene, highly expressed in the hippocampus, may regulate neuroinflammatory responses to Aβ deposition (Fani et al., 2022).
4. Neurogenesis and AD Progression
The dentate gyrus, a hippocampal subregion, is one of the few brain areas where adult neurogenesis occurs.
Neurogenesis declines significantly in AD, likely due to Aβ toxicity and tau pathology, impairing memory formation and plasticity (Terreros-Roncal et al., 2021).
Age-Related Cellular Changes in AD Mouse Models
A. AD Mouse Models: Aβ and Tau Pathology Over Time
AD mouse models reveal age-dependent changes in neurons, glia, and vascular cells.
Mouse Model Key Mutation(s) Pathology Onset Hippocampal Impact
APP/PS1 Mutant APP & PS1 3-6 months: Aβ plaques 9 months: Synaptic loss, microglial activation (Jankowsky et al., 2004)
5xFAD Multiple APP & PS1 mutations 2 months: Aβ accumulation 4-6 months: Neuronal death, 3 months: Astrocyte reactivity (Oakley et al., 2006)
P301S Tau Human Tau (P301S) 3-4 months: Hyperphosphorylated Tau 6 months: CA1 degeneration, microglial activation (Yoshiyama et al., 2007)
Pro-Inflammatory Age-Enriched Microglia Clusters in AD
Microglial Cluster Dynamics in AD
Model Age-Related Microglial Changes Key Markers
5xFAD Early microglial activation (3-6 months), chronic inflammation Trem2, Il1β, Ccl3, Lpl
APP/PS1 Age-dependent microglial clustering, impaired Aβ clearance Cd68, Itgax, Ccl4, Spp1
P301S Tau Increased pro-inflammatory clusters at 4-6 months Il6, Nos2, Cxcl10
Data Repositories & Datasets for AD Research
Single-Cell & Spatial Transcriptomics Datasets
Mouse Model Data
Therapeutic Implications: Targeting Age-Enriched Microglia
Potential Strategies
TREM2 Agonists: Boost Aβ phagocytosis, shifting microglia into a neuroprotective state (Ulland et al., 2017).
CSF1R Inhibitors: Reduce chronic microglial activation and prevent neurotoxic inflammation (Dagher et al., 2021).
IL-1β Inhibitors (Canakinumab): Block pro-inflammatory cytokines, preserving synapses (Deczkowska et al., 2020).
Gene Therapy Approaches: Modulate Mef2c, Apoe, and Trem2 to enhance microglial repair functions.
Conclusion
The hippocampus is highly vulnerable in Alzheimer’s disease (AD), serving as a central hub for memory formation, spatial navigation, and cognitive processing. As one of the earliest regions affected, it undergoes progressive degeneration due to amyloid-beta (Aβ) plaque accumulation, tau neurofibrillary tangles (NFTs), and chronic neuroinflammation. These pathological changes lead to early synaptic loss, neuronal death, and widespread network dysfunction, contributing to the cognitive impairments seen in AD patients.
One of the key findings from recent research is the emergence of pro-inflammatory microglial clusters in the hippocampus, which are characterized by elevated expression of Trem2, Il1β, Ccl3, and Lpl. While microglia initially play a protective role in Aβ clearance, their prolonged activation leads to chronic inflammation and impaired phagocytic function, ultimately exacerbating neuronal damage. Similarly, astrocytes undergo a reactive transformation, losing their neuroprotective properties and contributing to oxidative stress, blood-brain barrier (BBB) disruption, and synaptic dysfunction. At the same time, hippocampal neurogenesis, particularly in the dentate gyrus, declines significantly, further impairing the brain’s ability to compensate for neuronal loss.
Insights from AD mouse models (APP/PS1, 5xFAD, P301S Tau) reveal that age-related hippocampal dysfunction emerges as early as 3–6 months, highlighting a critical window for early intervention. Multi-omics approaches, including single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, have provided valuable insights into cell-type-specific vulnerabilities, paving the way for precision medicine approaches in AD treatment. TREM2 agonists and CSF1R inhibitors have shown potential in modulating microglial activation, while IL-1β inhibitors (e.g., Canakinumab) may help mitigate neuroinflammation and synaptic loss. Additionally, gene therapy strategies targeting hippocampal synaptic proteins such as NRGN, NECAB1, and CALB2 could help restore synaptic plasticity, while efforts to enhance dentate gyrus neurogenesis could improve memory function.
Future AD research must integrate early diagnostics, AI-driven molecular profiling, and neuroprotective therapeutics to slow hippocampal degeneration and preserve cognitive function. A multi-targeted approach that addresses synaptic dysfunction, neuroinflammation, and neurogenesis will be essential for developing effective AD treatments. By combining advancements in gene therapy, neuroregenerative strategies, and immune modulation, it may be possible to delay hippocampal atrophy and provide meaningful therapeutic benefits to AD patients.