Complexity of Sex Differences and Their Impact on Alzheimer’s Disease

Kadlecova, Marion; Freude, Kristine; Haukedal, Henriette

doi:10.3390/biomedicines11051261

Cited by 10 publications

(5 citation statements)

References 228 publications

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“…On the other hand, a lower SF would suggest a greater roughness compatible with the presence of numerous cellular processes, a morphology commonly found in non-pathological conditions (Kadlecova et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum

Lazzarini,

Gatta,

Miragliotta

et al. 2023

Journal of Anatomy

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Glial cells play a pivotal role in the inflammatory processes, which are common features of several neurodevelopmental and neurodegenerative disorders. Their major role in modulating neuroinflammation underscores their significance in these conditions. Engrailed‐2 knockout mice (En2−/−) are considered a valuable model for autism spectrum disorder (ASD) due to their distinctive neuroanatomical and behavioral traits. Given the higher prevalence of ASD in males, our objective was to investigate glial and interneuron alterations in the cerebellum of En2−/− mice compared with wild‐type (WT) mice in both sexes. We employed immunohistochemical analysis to assess cell density for all cell types studied and analyzed the area (A) and shape factor (SF) of microglia cell bodies. Our findings revealed the following: (a) In WT mice, the density of microglia and astrocytes was higher in females than in males, while interneuron density was lower in females. Notably, in En2‐mutant mice, these differences between males and females were not present. (b) In both male and female En2−/− mice, astrocyte density exceeded that in WT mice, with microglia density being greater only in females. (c) In WT females, microglia cell bodies exhibited a larger area and a lower shape factor compared to WT males. Remarkably, the En2 mutation did not appear to influence these sex‐related differences. (d) In both male and female En2−/− mice, we observed a consistent pattern: microglia cell bodies displayed a larger area and a smaller shape factor. Given the ongoing debate surrounding the roles of glia and sex‐related factors in ASD, our observations provide valuable insights into understanding how an ASD‐associated gene En2 affects specific cell types in the cerebellum.

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Section: Discussionmentioning

confidence: 99%

Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum

Lazzarini,

Gatta,

Miragliotta

et al. 2023

Journal of Anatomy

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“…IPSC‐derived brain cells show great research potential but have limitations that are applicable to the present model. Factors such as age, gender, or ethnicity can cause unexpected phenotypic changes after differentiation when using independent control donors (Haukedal et al., 2023; Kadlecova et al., 2023; Volpato & Webber, 2020), thus the use of isogenic controls, which genetically match the original cell source, could be a feasible solution. Besides, all iPSCs can reflect genetic variation inherited from the source cells or during reprogramming (Liang & Zhang, 2013).…”

Section: Discussionmentioning

confidence: 99%

Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC‐derived models of Alzheimer's disease

Salcedo,

Pozo Garcia,

García‐Adán

et al. 2023

Journal of Neurochemistry

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Glutamate recycling between neurons and astrocytes is essential to maintain neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in excitotoxicity and neuronal death, have been described as a potential mechanism in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter metabolism in different human brain cells, particularly astrocytes, has been poorly investigated at the early stages of AD. We sought to investigate glucose and glutamate metabolism in AD by employing human induced pluripotent stem cell (hiPSC)‐derived astrocytes and neurons carrying mutations in the amyloid precursor protein (APP) or presenilin‐1 (PSEN‐1) gene as found in familial types of AD (fAD). Methods such as live‐cell bioenergetics and metabolic mapping using [13C]‐enriched substrates were used to examine metabolism in the early stages of AD. Our results revealed greater glycolysis and glucose oxidative metabolism in astrocytes and neurons with APP or PSEN‐1 mutations, accompanied by an elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or PSEN‐1 mutations exhibited reduced expression of the excitatory amino acid transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with enhanced glutamate release specifically in neurons with a PSEN‐1 mutation. These results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations possibly linked to toxic glutamate accumulation. Our findings further identify metabolic imbalances that may occur in the early phases of AD pathophysiology.

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“…Several epidemiological studies have suggested that the use of estrogen therapy among women who have undergone menopause may have demonstrated a preventive, therapeutic or potentially delaying effect on the onset of AD (Bolt et al, 2024). A notable study has indicated that the hormone estrogen possesses the capability to augment the effectiveness of tacrine, an anticholinesterase pharmaceutical utilised for the treatment of AD (Kadlecova et al, 2023).…”

Section: Therapeutic Strategies Targeting Estrogens To Mitigate the E...mentioning

confidence: 99%

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough

Rishabh,

Rohilla,

Bansal

et al. 2024

Eur J of Neuroscience

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In females, Alzheimer's disease (AD) incidences increases as compared to males due to estrogen deficiency after menopause. Estrogen therapy is the mainstay therapy for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. Estrogen plays a crucial role in amyloid precursor protein (APP) processing and overall neuronal health by regulating various factors such as brain‐derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain‐associated protein (Daxx) translocation, glutamatergic excitotoxicity, Voltage‐Dependent Anion Channel, Insulin‐Like Growth Factor 1 Receptor, estrogen‐metabolising enzymes and apolipoprotein E (ApoE) protein polymorphisms. All these factors impact the physiology of postmenopausal women. Estrogen replacement therapies play an important treatment strategy to prevent AD after menopause. However, use of these therapies may lead to increased risks of breast cancer, venous thromboembolism and cardiovascular disease. Various therapeutic approaches have been used to mitigate the effects of estrogen on AD. These include hormone replacement therapy, Selective Estrogen Receptor Modulators (SERMs), Estrogen Receptor Beta (ERβ)‐Selective Agonists, Transdermal Estrogen Delivery, Localised Estrogen Delivery, Combination Therapies, Estrogen Metabolism Modulation and Alternative Estrogenic Compounds like genistein from soy, a notable phytoestrogen from plant sources. However, mechanism via which these approaches modulate AD in postmenopausal women has not been explained earlier thoroughly. Present review will enlighten all the molecular mechanisms of estrogen and estrogen replacement therapies in AD. Along‐with this, the association between estrogen, estrogen‐metabolising enzymes and ApoE protein polymorphisms will also be discussed in postmenopausal AD.

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Complexity of Sex Differences and Their Impact on Alzheimer’s Disease

Cited by 10 publications

References 228 publications

Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum

Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum

Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC‐derived models of Alzheimer's disease

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough

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