Role of Microglia in Regulating Cholesterol and Tau Pathology in Alzheimer’s Disease

Nanjundaiah, Shwetha; Chidambaram, Hariharakrishnan; Chandrashekar, Madhura; Chinnathambi, Subashchandrabose

doi:10.1007/s10571-020-00883-6

Cited by 15 publications

(7 citation statements)

References 222 publications

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“…There is now a considerable literature on how cholesterol and ApoE interact with Abeta synthesis and transport, APP metabolism, amyloid formation and tau phosphorylation (Michikawa, 2006;Carter, 2007;Popp et al, 2013;Allinquant et al, 2014;Gamba et al, 2015;Sun et al, 2015;Fanaee-Danesh et al, 2019;Loera-Valencia et al, 2019;Chew et al, 2020;Chai et al, 2021;Nanjundaiah et al, 2021;Wu et al, 2022). In general higher plasma and brain cholesterol and its metabolites correlate with higher brain Abeta levels and lower CSF Abeta levels (Reed et al, 2014;Iriondo et al, 2020).…”

Section: Myelin Injury Coupled With Cholesterol Dysmetabolism Contrib...mentioning

confidence: 99%

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Sharp

DeCarli

Jin

et al. 2023

Front. Aging Neurosci.

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We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer’s disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer’s initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer’s disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

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Section: Myelin Injury Coupled With Cholesterol Dysmetabolism Contrib...mentioning

confidence: 99%

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Sharp

DeCarli

Jin

et al. 2023

Front. Aging Neurosci.

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“…Furthermore, in our study, after silencing DHCR24 by lentivirus-mediated DHCR24 short hairpin RNA (shRNA) in SH-SY5Y cells, we found silencing DHCR24 could markedly induce hyperphosphorylation of tau at some specific sites, including Thr181, Ser199, Thr231, Ser262, Ser396, and Ser422 [ 9 , 119 ]. Besides, we further found that DHCR24 knockdown lead to the decrease of plasma membrane cholesterol and disruption of lipid raft/caveolae, resulting in inhibition of lipid raft-dependent phosphoinositide 3-kinase (PI3-K)/ protein kinase B (Akt) signaling, Protein phosphatase 2A (PP2A) signaling, as well as the overactivation of glycogen synthase kinases-3beta (GSK3β) and mammalian target of rapamycin (mTOR) signaling [ 9 , 103 , 119 ]. Similarly, defects in the cholesterol trafficking are associated with enhanced generation of hyperphosphorylated Tau and Amyloid-β protein [ 131 ].…”

Section: Dhcr24 Downregulation and Pathological Impairments Related T...mentioning

confidence: 99%

The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis

Bai

Mai

Yao

et al. 2022

acta neuropathol commun

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Previous studies show that 3β-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In brain cholesterol synthetic metabolism, DHCR24 is known as the heavily key synthetase in cholesterol synthesis. Moreover, mutations of DHCR24 gene result in inhibition of the enzymatic activity of DHCR24, causing brain cholesterol deficiency and desmosterol accumulation. Furthermore, in vitro studies also demonstrated that DHCR24 knockdown lead to the inhibition of cholesterol synthesis, and the decrease of plasma membrane cholesterol and intracellular cholesterol level. Obviously, DHCR24 could play a crucial role in maintaining cholesterol homeostasis via the control of cholesterol synthesis. Over the past two decades, accumulating data suggests that DHCR24 activity is downregulated by major risk factors for AD, suggesting a potential link between DHCR24 downregulation and AD pathogenesis. Thus, the brain cholesterol loss seems to be induced by the major risk factors for AD, suggesting a possible causative link between brain cholesterol loss and AD. According to previous data and our study, we further found that the reduced cholesterol level in plasma membrane and intracellular compartments by the deficiency of DHCR24 activity obviously was involved in β-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal that the brain cholesterol loss and lipid raft disorganization are obviously linked to neuropathological impairments which are associated with AD pathogenesis. Therefore, based on previous data and research on DHCR24, we suppose that the brain cholesterol deficiency/loss might be involved in the pathogenesis of AD.

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“…In the latter study, the R47H mutation resulted in reduced clustering of microglia at plaques but critically did not impair the formation of lipid droplets within individual cells. Microglia also appear active in the regulation of cholesterol-modulated phosphotau pathology through activation and phagocytic pathways ( Nanjundaiah et al, 2021 ). Excess cholesterol and other lipids are detected by microglial TREM2 (amongst other receptors) when complexed with apolipoproteins (such as APOE or APOJ) which in turn activates the PI3K/AKT/mTOR signalling cascade ( Peng et al, 2010 ) which is linked to the inhibition of GSK3β ( Hermida et al, 2017 )—an important mediator of intraneuronal tau hyperphosphorylation ( Hooper et al, 2008 ).…”

Section: Lipids In Alzheimer’s Diseasementioning

confidence: 99%

Synapses, Microglia, and Lipids in Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is characterised by synaptic dysfunction accompanied by the microscopically visible accumulation of pathological protein deposits and cellular dystrophy involving both neurons and glia. Late-stage AD shows pronounced loss of synapses and neurons across several differentially affected brain regions. Recent studies of advanced AD using post-mortem brain samples have demonstrated the direct involvement of microglia in synaptic changes. Variants of the Apolipoprotein E and Triggering Receptors Expressed on Myeloid Cells gene represent important determinants of microglial activity but also of lipid metabolism in cells of the central nervous system. Here we review evidence that may help to explain how abnormal lipid metabolism, microglial activation, and synaptic pathophysiology are inter-related in AD.

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Role of Microglia in Regulating Cholesterol and Tau Pathology in Alzheimer’s Disease

Cited by 15 publications

References 222 publications

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis

Synapses, Microglia, and Lipids in Alzheimer’s Disease

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