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

Rao, Y. Lakshmisha; Ganaraja, B; Nayak, Vanishri S.; Joy, Teresa; Krishnamurthy, Arvind; Agrawal, Amit

doi:10.1007/s13205-022-03123-4

Cited by 177 publications

(109 citation statements)

References 96 publications

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“…In particular, the areas in the right medial temporal gyrus (BA20/21) were thinner in both AD-HCR and a-MCI-HCR. These brain areas are known to be crucial for long-term memory, and the present results reinforce the idea that they are involved since early stages of AD [46][47]. However, some cortical areas showed different anatomical patterns of atrophy in patients with AD and a-MCI.…”

Section: Discussionsupporting

confidence: 87%

Cognitive Reserve Modulates Brain Structure and Cortical Architecture in the Alzheimer’s Disease

Serra

Giancaterino

Giulietti

et al. 2022

JAD

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Background: Cognitive reserve (CR) explains the individual resilience to neurodegeneration. Objective: The present study investigated the effect of CR in modulating brain cortical architecture. Methods: 278 individuals [110 Alzheimer’s disease (AD), 104 amnestic mild cognitive impairment (aMCI) due to AD, 64 healthy subjects (HS)] underwent a neuropsychological evaluation and 3T-MRI. Cortical thickness (CTh) and fractal dimension (FD) were assessed. Years of formal education were used as an index of CR by which participants were divided into high and low CR (HCR and LCR). Within-group differences in cortical architecture were assessed as a function of CR. Associations between cognitive scores and cortical measures were also evaluated. Results: aMCI-HCR compared to aMCI-LCR patients showed significant decrease of CTh in the right temporal and in the left prefrontal lobe. Moreover, they showed increased FD in the right temporal and in the left temporo-parietal lobes. Patients with AD-HCR showed reduced CTh in several brain areas and reduced FD in the left temporal cortices when compared with AD-LCR subjects. HS-HCR showed a significant increase of CTh in prefrontal areas bilaterally, and in the right parieto-occipital cortices. Finally, aMCI-HCR showed significant positive associations between brain measures and memory and executive performance. Conclusion: CR modulates the cortical architecture at pre-dementia stage only. Indeed, only patients with aMCI showed both atrophy (likely due to neurodegeneration) alongside richer brain folding (likely due to reserve mechanisms) in temporo-parietal areas. This opposite trend was not observed in AD and HS. Our data confirm the existence of a limited time-window for CR modulation at the aMCI stage.

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Section: Discussionsupporting

confidence: 87%

Cognitive Reserve Modulates Brain Structure and Cortical Architecture in the Alzheimer’s Disease

Serra

Giancaterino

Giulietti

et al. 2022

JAD

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“…The hippocampus plays a major role in memory. It is one of the few regions of the brain that sustains neurogenesis in adulthood, and there is loss of neurons in that area in Alzheimer’s disease ( Rao YL, et al, 2022 ). Remarkably, recent work indicates that Klotho stimulates neurogenesis in the hippocampus.…”

Section: Klotho and Neurodegenerative Diseasesmentioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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“…The hippocampus, the brain structure responsible for various cognitive functions that depend on adult neurogenesis and synaptic plasticity, is one of the earliest affected brain regions in AD, and its dysfunction is believed to underlie the core feature of the disease-associated memory impairment (Rao et al 2022). Reduced levels of CX3CL1 were found in the hippocampus and frontal cortex of AD patients as compared to healthy controls (Cho et al 2011), and in the CSF of patients with MCI and AD dementia (Perea et al 2018).…”

Section: Cx3cl1 (Fractalkine)mentioning

confidence: 99%

Role of Chemokines in the Development and Progression of Alzheimer’s Disease

2022

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Alzheimer’s disease (AD) is a progressive neurogenerative disorder manifested by gradual memory loss and cognitive decline due to profound damage of cholinergic neurons. The neuropathological hallmarks of AD are intracellular deposits of neurofibrillary tangles (NFTs) and extracellular aggregates of amyloid β (Aβ). Mounting evidence indicates that intensified neuroinflammatory processes play a pivotal role in the pathogenesis of AD. Chemokines serve as signaling molecules in immune cells but also in nerve cells. Under normal conditions, neuroinflammation plays a neuroprotective role against various harmful factors. However, overexpression of chemokines initiates disruption of the integrity of the blood–brain barrier, facilitating immune cells infiltration into the brain. Then activated adjacent glial cells–astrocytes and microglia, release massive amounts of chemokines. Prolonged inflammation loses its protective role and drives an increase in Aβ production and aggregation, impairment of its clearance, or enhancement of tau hyperphosphorylation, contributing to neuronal loss and exacerbation of AD. Moreover, chemokines can be further released in response to growing deposits of toxic forms of Aβ. On the other hand, chemokines seem to exert multidimensional effects on brain functioning, including regulation of neurogenesis and synaptic plasticity in regions responsible for memory and cognitive abilities. Therefore, underexpression or complete genetic ablation of some chemokines can worsen the course of AD. This review covers the current state of knowledge on the role of particular chemokines and their receptors in the development and progression of AD. Special emphasis is given to their impact on forming Aβ and NFTs in humans and in transgenic murine models of AD.

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

Cited by 177 publications

References 96 publications

Cognitive Reserve Modulates Brain Structure and Cortical Architecture in the Alzheimer’s Disease

Cognitive Reserve Modulates Brain Structure and Cortical Architecture in the Alzheimer’s Disease

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Role of Chemokines in the Development and Progression of Alzheimer’s Disease

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