Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. One of the key pathological hallmarks of AD is the accumulation of amyloid beta (Aβ), a peptide derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases [1]. Aβ aggregates in the brain, forming extracellular amyloid plaques that contribute to synaptic dysfunction, neuroinflammation, and neuronal death [1]. While Aβ has long been recognized for its detrimental effects on neuronal function, emerging evidence suggests that it may also have complex and context-dependent roles in neurogenesis. In this brief review, we explore the multifaceted actions of Aβ on hippocampal neurogenesis in the context of AD pathogenesis. We discuss the molecular pathways through which Aβ influences neuronal development, examine its contrasting effects on neurogenesis, and consider potential implications for therapeutic interventions aimed at preserving or enhancing hippocampal function in AD patients. Understanding these intricate mechanisms may provide critical insights into the development of more effective treatment strategies for AD.

As described earlier, Aβ is a key pathological protein that is involved in AD pathogenesis. Aβ can alter neuronal physiology through various mechanisms. For example, Aβ modulates synaptic transmission, but concentrations outside the physiological range disrupt synaptic function [2]. Aβ also induces tau hyperphosphorylation [3,4], a hallmark of AD closely linked to neuronal loss and cognitive decline [5]. This process is particularly important in pathogenesis of AD, as Aβ accelerates spatial spreading of tau pathology [6]. Aβ-induced tau hyperphosphorylation is mediated by interaction with various neuronal receptors including plexin-A4 [7]. Furthermore, Aβ generates oxidative stress in neurons via free radical production, eventually leading to neuronal death [8]. It can also directly damage cellular membranes and dysregulate intracellular calcium levels [9]. Collectively, these findings underscore the significant role of Aβ in the neuronal pathophysiology of AD.

The hippocampus, a brain region essential for learning and memory, is particularly vulnerable to AD pathology. Importantly, it is also one of the few areas in the adult brain where neurogenesis occurs. Adult hippocampal neurogenesis (AHN) involves the generation of new neurons from neural stem cells (NSCs) in the subgranular zone of the hippocampus [10]. At first glance, enhancing hippocampal neurogenesis might seem like a promising strategy to repair the hippocampus in AD patients and reverse cognitive decline. Indeed, promoting hippocampal neurogenesis alongside increasing brain-derived neurotrophic factor (BDNF) levels has been shown to alleviate cognitive decline in mouse models of AD [11]. Infusion of nerve growth factor (NGF), another critical neurotrophic factor, also improved memory [12], while the neurotrophic hormone ghrelin also rescued hippocampal neurogenesis and cognitive decline in AD mouse model [13,14]. However, accumulating evidence suggests that this process is far more complex. Hippocampal neurogenesis is significantly reduced in AD patients compared to healthy individuals [15], making it difficult to generate sufficient neurons for recovery. Aβ appears to be a major contributor to this impaired neurogenesis.

Our research group previously demonstrated that mitochondria-specific accumulation of Aβ leads to mitochondrial dysfunction [16], which in turn suppresses hippocampal neurogenesis [17]. Specifically, mitochondrial dysfunction triggers the proteasomal degradation of transcription factor KDM5A, reducing the expression of downstream genes, including neuronal differentiation factors such as BDNF and MEF2A. There are some noteworthy aspects from the study. The target of Aβ-mediated mitochondrial dysfunction was discovered with unbiased proteomic and phospho-proteomic analysis, emphasizing the importance of KDM5A in dysregulation of hippocampal neurogenesis by Aβ. Secondly, while the differentiation process was impaired by Aβ-mediated mitochondrial dysfunction, proliferation and viability of NSCs were relatively intact. This implies that the reservoir of hippocampal NSCs might be preserved in early stage of AD, thus modulation of neuronal differentiation can rescue impaired neurogenesis, possibly by controlling KDM5A level. Another study reported that Aβ directly impairs BDNF signaling via modulation of its receptor, TrkB [18]. Treatment of fibrillar/protofibrillar Aβ peptide led to calpain-mediated cleavage of TrkB, thereby compromising signaling pathways through its intracellular domain. BDNF-TrkB signaling can affect mitochondrial metabolism and dynamics via various intracellular signaling cascades including cAMP-PKA-CREB pathway, PI3K-Akt pathway, and Ras-Raf-MEK-ERK pathway [19,20] Together with the effect on KDM5A degradation, Aβ inhibits the neurotrophic effects of BDNF by suppressing its expression and disrupting its signaling cascades, impairing mitochondrial function. Recent findings provide further evidence of Aβ's detrimental effects on hippocampal neurogenesis. Chiara et al. showed that upregulated JUN in neuronal progenitor cells derived from familial AD patients disrupts neurogenesis by dysregulating transposable elements [21]. Upregulated JUN led to increased mobilization of transposable elements, which resulted in accumulation of RNA-DNA hybrids that activate cGAS-STING pathway. Notably, aggregated Aβ induces JUN expression, whereas non-aggregated Aβ does not produce this effect [22]. Aβ also disrupts other signaling pathways critical to neurogenesis. For instance, Wnt signaling is downregulated by Aβ binding to the Wnt receptor Frizzled [23], and Shh signaling is similarly impaired by Aβ 1-42 [24]. These pathways are essential for maintenance and proliferation of hippocampal NSCs [25]. A recent study reported that a neurokinin-3 receptor (NK3R) agonist rescued Aβ-induced cognitive impairment by promoting hippocampal neurogenesis in a rat model, although the specific intracellular signaling pathway involved remains unclear [26]. Recently, a small molecule named KARI 201 was developed, which acts as both an acid sphingomyelinase (ASM) inhibitor and a growth hormone secretagogue receptor 1α (GHSR1α) agonist [27]. KARI 201 was found to rescue Aβ-induced reductions in the proliferation and survival of hippocampal NSCs. Previous studies revealed that ASM levels are elevated in AD patients and mouse models, likely due to Aβ deposition [28]. Increased ASM leads to higher ceramide production, which impairs hippocampal neurogenesis [29]. On the other hand, ghrelin, the ligand of GHSR1α, promotes hippocampal neurogenesis, especially in its acylated form [30,31]. Interestingly, Aβ directly inhibits GHSR1α activity, thereby inhibiting its downstream signaling pathway [32]. These findings highlight the roles of both ASM and GHSR1α signaling in Aβ-induced impairment of hippocampal neurogenesis.

While aggregated forms of Aβ are highly toxic to neurons, soluble Aβ plays several physiological roles, including modulating synaptic function and providing protection against oxidative stress and pathogens [1]. Notably, Aβ has also been shown to promote neuronal growth and survival. Contrary to the detrimental effect of aggregated forms, soluble Aβ has been reported to stimulate hippocampal neurogenesis.

Early studies revealed that truncated forms of Aβ, such as Aβ 25-35 and Aβ 1-28, exhibit neurotrophic effects [33,34]. A 2009 study demonstrated that monomeric Aβ 1-42 enhances neuronal survival by activating the PI3K-Akt pathway [35], a critical signaling pathway for neurogenesis and neuronal differentiation [36]. Another study reported increased proliferation of NSCs following Aβ treatment, with Aβ 1-42 exhibiting a greater neurogenic effect than Aβ 1-40 [37]. In this study, inhibition of tyrosine kinase or MEK abolished the neurogenic effect of Aβ, suggesting the involvement of Ras-Raf-MEK-ERK pathway in Aβ-induced neurogenesis. Notably, while oligomeric Aβ 1-42 increased neurogenesis, Aβ 1-42 fibril did not show that effect. Meanwhile, PI3K-Akt pathway and Ras-Raf-MEK-ERK pathway are important regulators of mitochondrial metabolism [20], suggesting possible involvement of mitochondrial change in soluble Aβ-mediated hippocampal neurogenesis. These findings are particularly surprising, given the high aggregation tendency and cytotoxicity of Aβ 1-42 and its strong association with clinical status of AD [1,38]. It remains unclear whether the observed increase in neurogenesis is a compensatory response to neuronal damage or an intrinsic property of Aβ. Nonetheless, it is evident that the concentration and aggregation state of Aβ are critical factors influencing the fate of hippocampal NSCs. This dual role of Aβ in neurogenesis highlights the complexity of its impact on brain function and suggests that therapeutic strategies targeting Aβ must be carefully designed to preserve potential beneficial effects while mitigating its toxicity.

Currently, the only approved class of disease-modifying drug for AD is anti-Aβ antibody. By removing amyloid plaques in the brain, anti-Aβ antibody have proven their ability to delay cognitive decline. Lecanemab and Donanemab have gained approval and are being used in multiple countries worldwide. Despite the success of these anti-Aβ antibodies, there are critical limitations to overcome. The antibodies are not eligible for every patients, especially due to its side effect. Amyloid-related imaging abnormalities (ARIA) are major side effects of anti-Aβ antibodies, causing edema (ARIA-E) or hemorrhage (ARIA-H) in the brain parenchyme [39].

Patients with cerebral amyloid angiopathy (CAA), ones at high risk of bleeding, and ApoE ε4 homozygotes are at high risk of severe ARIA [39]. Additionally, Lecanemab and Donanemab could not completely stop the progression of AD; 27% slower cognitive decline by Lecanemab and 35% by Donanemab [40,41]. These practical limitations impose urgent need for other treatment options of AD. Efforts to reverse cognitive decline in AD patients, such as stem cell transplantation, are ongoing [42]. Exogenous supplementation of stem cells can be effective in some patients who have little hippocampal NSCs remaining. However, stem cell transplantation has substantial side effects, such as rejection, immune reaction, and tumorigenesis [43]. Efficacy of delivery and engraftment, survival of transplanted cells are also major clinical issues of consideration. Therefore, reinforcing functions of remaining hippocampal NSCs can be a better option in many cases, especially for patients who have relatively intact reservoir of the NSCs. There are two ongoing clinical trials aiming to enhance hippocampal neurogenesis. One is a phase 2 clinical trial (NCT04052737) of a drug Sovateltide (PMZ-1620), an endeothelin B receptor agonist which can increase neurogenesis and vasculogenesis by elevating NGF and vascular endothelial growth factor (VEGF) [44]. The other one is a phase 2 trial of Allopregnanolone (NCT04838301), a neuroactive progesterone metabolite that increases proliferation of NSCs [45]. The outcomes of these clinical trials will shed light on whether enhancing hippocampal neurogenesis could be an effective treatment strategy for AD. Besides, several preclinical studies have suggested other possible options of boosting hippocampal neurogenesis to delay cognitive decline [12-14]. Despite all these efforts, the feasibility of achieving true cognitive reversal remains uncertain. Additionally, selection of patients with sufficient reservoir of hippocampal NSCs would be critical to the therapeutic strategy. Development of screening method to assess the quantity and pluripotency of NSCs should proceed in parallel with drug development to ensure effective treatment for the right patients at the right time. Further preclinical and clinical studies will be essential to address these challenges.

AD is characterized not only by neuronal loss but also by insufficient neurogenesis to compensate for the damage. Aβ contributes to the pathogenesis of AD by impairing hippocampal neurogenesis through multiple mechanisms. While most studies highlight its detrimental effects, several reports suggest that Aβ also has protective roles under certain conditions. Thus, therapeutic approaches aimed at reducing Aβ levels, such as β- and γ-secretase inhibitors, may not be universally effective.

Key questions remain: What is the critical threshold of Aβ accumulation? How do factors such as Aβ oligomerization, aggregation, and the balance between Aβ 1-42 and Aβ 1-40 contribute to early AD pathogenesis? Future research should focus on the spatiotemporal dynamics of Aβ deposition and its impact on neuronal health and neurogenesis in the earliest stages of AD. Understanding these mechanisms could lead to the development of effective therapies to halt AD progression.

This research was supported by a grant of the MD-Phd/Medical Scientist Training Program through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea.

This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare and Ministry of science and ICT, Republic of Korea (grant number: RS-2020-KH106773) for Inhee Mook-Jung.