Is Alzheimer’s Disease a Neurogenesis Disorder?

Choi, Se Hoon; Tanzi, Rudolph E.

doi:10.1016/j.stem.2019.06.001

“…This is evident of the controversial studies that showed AD to downregulate hippocampal neurogenesis with progression of disease [46] or to increase hippocampal neurogenesis [47]. Nevertheless, disruption of AHN at early stages might mediate the AD pathogenesis, indicating a therapeutic approach towards its prevention and treatment [48].…”

Section: Evidence Of Hmgb1 Implication In Ad Pathogenesismentioning

confidence: 99%

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Paudel

¹

,

Angelopoulou

²

,

Piperi

³

et al. 2020

Cells

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

show abstract

“…Adult neurogenesis is an extremely vulnerable process, which is prone to alterations under numerous physiological and pathological conditions. Several lines of evidence suggest a substantial impairment of neurogenesis in AD, which is one of the earliest pathological characteristics of the disease, and its manipulation has been pursued as a potential therapeutic strategy [64].…”

Section: Discussionmentioning

confidence: 99%

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Polis

¹

,

Srikanth

²

,

Gurevich

³

et al. 2020

IJMS

View full text Add to dashboard Cite

Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.

show abstract

“…Adult neurogenesis is an extremely vulnerable process, which is prone to alterations under numerous physiological and pathological conditions. Several lines of evidence suggest a substantial impairment of neurogenesis in AD, which is one of the earliest pathological characteristics of the disease, and its manipulation has been pursued as a potential therapeutic strategy [54].…”

Section: Discussionmentioning

confidence: 99%

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Polis

¹

,

Gurevich

²

,

Bloch

³

et al. 2019

Preprint

1

0

View full text Add to dashboard Cite

Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer's disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis.Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administer an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and apply an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy.Remarkably, we evidence a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline shows no significant effect upon the progenitor cell number and constitution. We demonstrate that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identify a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.However, the existence of human adult neurogenesis has been a subject of intense scientific debate, until recently. Tobin et al. (2019) evidenced hippocampal neurogenesis persisting throughout life in the brains of centenarians and even of Alzheimer's disease (AD) patients [2]. Convincingly, they demonstrated that the density of NPCs, neuroblasts, and immature neurons significantly decreases in cases of mild cognitive impairment and in clinical AD as compared to healthy controls. In addition, various animal models of AD are characterized by diminished adult neurogenesis. In particular, triple-transgenic mice (3×Tg) show an age-dependent neurogenesis insufficiency that is detectable in the hippocampus starting at four months of age [3]. Of note, the decline of neurogenesis in this AD model precedes the manifestation of classical hallmarks of AD pathology, such as deposition of amyloid plaques and neurofibrillary tangles in the brain, as well as memory impairment. Remarkably, as a form of neuroplasticity, adult neurogenesis has been shown to modulate vulnerability to degenerative processes and influence the course of AD [4]. Moreover, various supporting adult neurogenesis treatment strategies have demonstrated their competence to counteract the pathological behavioral outcomes in murine AD models [5]. Nevertheless, the mechanisms that regulate NPC proliferation, ...

show abstract

Is Alzheimer’s Disease a Neurogenesis Disorder?

Cited by 69 publications

References 10 publications

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Contact Info

Product

Resources

About