Brain Inflammation, Cholesterol, and Glutamate as Interconnected Participants in the Pathology of Alzheimers Disease

Ringheim, Garth E.; Am, Szczepanik

doi:10.2174/138161206775474215

Cited by 25 publications

(22 citation statements)

References 294 publications

(368 reference statements)

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“…NMDARs are one of the major glutamate-activated ionotropic receptors in the brain and are permeable to sodium, potassium, and calcium. Compromised neuronal viability due to excessive NMDAR activation has been described in several neurodegenerative diseases (34,35) including HIV dementia (36). We demonstrate the contribution of activated NMDARs as part of the tat-LRP-PSD-95-NMDAR-nNOS macromolecular complex to tatinduced apoptosis, and identify NO as a major downstream effector.…”

Section: Discussionmentioning

confidence: 63%

HIV-tat induces formation of an LRP–PSD-95– NMDAR–nNOS complex that promotes apoptosis in neurons and astrocytes

Eugenín¹,

King²,

Nath

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

188

222

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HIV infection of the central nervous system can result in neurologic dysfunction with devastating consequences in AIDS patients. NeuroAIDS is characterized by neuronal injury and loss, yet there is no evidence that HIV can infect neurons. Here we show that the HIV-encoded protein tat triggers formation of a macromolecular complex involving the low-density lipoprotein receptor-related protein (LRP), postsynaptic density protein-95 (PSD-95), N-methyl-D-aspartic acid (NMDA) receptors, and neuronal nitric oxide synthase (nNOS) at the neuronal plasma membrane, and that this complex leads to apoptosis in neurons negative as well as positive for NMDA receptors and also in astrocytes. Blockade of LRPmediated tat uptake, NMDA receptor activation, or neuronal nitric oxide synthase significantly reduces ensuing neuronal apoptosis, suggesting that formation of this complex is an early step in tat toxicity. We also show that the inflammatory chemokine, CCL2, protects against tat toxicity and inhibits formation of the complex. These findings implicate the complex in HIV-induced neuronal apoptosis and suggest therapeutic targets for intervention in the pathogenesis of NeuroAIDS.glutamate ͉ dementia ͉ HIV-1 ͉ NeuroAIDS ͉ excitotoxicity H IV enters the CNS early after infection. Viral persistence within the CNS can produce cognitive impairment, HIV encephalitis, and, in some cases, dementia. NeuroAIDS is characterized by neuronal damage and loss and cognitive and motor deficits and can have devastating consequences in a significant number of individuals with AIDS. As HIV-infected individuals live longer on antiretroviral therapy, the prevalence of cognitive impairment is increasing, and the study of the pathogenesis of NeuroAIDS becomes even more critical (1, 2).Although HIV infection of the CNS causes neuronal cell damage and loss, the virus cannot directly infect neurons. Rather, HIV-associated damage is thought to be due to an indirect mechanism whereby virally infected, as well as uninfected, cells elaborate neurotoxins. Candidate toxins include cytokines, glutamate, and virally encoded proteins such as the HIV transactivator protein, tat (3). Tat potentiates glutamateinduced excitotoxicity (4, 5) and promotes neuronal apoptosis (6-8). Antagonists of the N-methyl-D-aspartic acid (NMDA) receptor (NMDAR) protect against tat-induced apoptosis (5, 7), implicating NMDARs in this process.The low-density lipoprotein receptor-related protein (LRP) is expressed by many cells in the CNS, including neurons and astrocytes (9, 10). LRP is a receptor for at least 16 endogenous ligands and also for the viral protein tat, and mediates uptake of these ligands into endosomes in various cells, including neurons (9). Tat and some other LRP ligands can activate NMDARs and mediate calcium signaling in neurons (4,11,12). Tat, in contrast to other LRP ligands, escapes from the endosomal/lysosomal compartment (9) and, by mechanisms still poorly known, induces apoptosis in both neurons and astrocytes.This study was undertaken to examine mechanisms by...

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Section: Discussionmentioning

confidence: 63%

HIV-tat induces formation of an LRP–PSD-95– NMDAR–nNOS complex that promotes apoptosis in neurons and astrocytes

Eugenín¹,

King²,

Nath

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

188

222

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“…Numerous hypotheses have been proposed to explain the pathogenesis of AD, including altered APP processing and amyloid toxicity, 46,47 tau hyperphosphorylation, 48 altered lipid, 49 cholesterol, 50 and glucose 51 metabolism, aberrant calcium homeostasis, 52 glutamate excitotoxicity, 53 inflammation, 53 and mitochondrial dysfunction and oxidative stress. 45 A localization of presenilin in MAM, a compartment intimately involved in lipid, glucose, cholesterol, and calcium homeostasis, may help reconcile these disparate hypotheses, and could explain many seemingly unrelated features of this devastating neurodegenerative disorder.…”

Section: Discussionmentioning

confidence: 99%

Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria

Area‐Gómez

Groof

Boldogh

et al. 2009

The American Journal of Pathology

350

305

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Presenilin-1 (PS1) and -2 (PS2), which when mutated cause familial Alzheimer disease, have been localized to numerous compartments of the cell, including the endoplasmic reticulum, Golgi, nuclear envelope, endosomes, lysosomes, the plasma membrane, and mitochondria. Using three complementary approaches, subcellular fractionation, ␥-secretase activity assays, and immunocytochemistry, we show that presenilins are highly enriched in a subcompartment of the endoplasmic reticulum that is associated with mitochondria and that forms a physical bridge between the two organelles, called endoplasmic reticulum-mitochondria-associated membranes. A localization of PS1 and PS2 in mitochondria-associated membranes may help reconcile the disparate hypotheses regarding the pathogenesis of Alzheimer disease and may explain many seemingly unrelated features of this devastating neurodegenerative disorder. Alzheimer disease (AD) is a late onset neurodegenerative disorder characterized by progressive neuronal loss, especially in the cortex and the hippocampus. 1 The two main histopathological hallmarks of AD are the accumulation of extracellular neuritic plaques, consisting predominantly of ␤-amyloid (A␤), and of neurofibrillary tangles, consisting mainly of hyperphosphorylated forms of the microtubule-associated protein tau. 1The vast majority of AD is sporadic, but mutations in amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2) have been identified in the rarer familial form, which is similar to sporadic AD but has an earlier age of onset.PS1 and PS2 are aspartyl proteases that cleave their substrates within transmembrane regions. The active forms of PS1 and PS2 are N-and C-terminal fragments, which are produced by cleavage of full-length presenilin in its "loop" domain.2 PS1 and PS2 are components of the ␥-secretase complex that processes a number of plasma-membrane proteins, including Notch, Jagged, E-cadherin, and, most relevant to AD, APP. The ␥-secretase complex also contains three other structural subunits: APH1, nicastrin (also called APH2), and presenilin enhancer protein 2.2 Following cleavage of APP by ␤-secretase, ␥-secretase cleaves the ϳ100-aa C-terminal "␤-stub" to release small amyloidogenic fragments, 40-and 42-aa in length (A␤40 and A␤42), that have been implicated in the pathogenesis of AD, as well as a ϳ60-aa APP intracellular domain.

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“…These features of AD have received far less attention because of the lack of direct links to the amyloid cascade, and have engendered numerous competing hypotheses to explain the pathogenesis of AD. These include tau hyperphosphorylation [12], altered lipid [13], cholesterol [14], and glucose metabolism [15,16], aberrant calcium homeostasis [17], glutamate excitotoxicity [18], inflammation [18,19], ER stress and the unfolded protein response (UPR) [20][21][22][23], and mitochondrial dysfunction and oxidative stress [24]. It remains to be determined to what degree these phenomena are causally interlinked, and whether they may be direct outcomes of defects in AβPP processing.…”

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confidence: 99%

Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

Schon

Area‐Gómez

2010

JAD

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Abstract. The subcellular localization of presenilin-1 (PS1) and presenilin-2 (PS2), two proteins that, when mutated, cause familial Alzheimer's disease (AD), is controversial. We have discovered that mitochondria-associated membranes (MAM) -a specialized subcompartment of the endoplasmic reticulum (ER) involved in lipid metabolism and calcium homeostasis that physically connects ER to mitochondria -is the predominant subcellular location for PS1 and PS2, and for γ-secretase activity. We hypothesize that presenilins play a role in maintaining MAM function, and that not only altered amyloid-β levels and hyperphosphorylated tau, but also many other features of AD (e.g., altered phospholipid and cholesterol metabolism, aberrant calcium homeostasis, and abnormal mitochondrial dynamics) result from compromised MAM function. The localization of presenilins and γ-secretase in MAM may help reconcile disparate ideas regarding the pathogenesis of AD, under a unifying hypothesis that could explain many features of both sporadic and familial AD, thereby taking AD research in a new and fruitful direction.Keywords: Alzheimer's disease, calcium, cholesterol, endoplasmic reticulum (ER), mitochondria, mitochondria-associated membranes (MAM), phospholipids ALZHEIMER'S DISEASEAlzheimer's disease (AD), the most common late onset neurodegenerative dementing disorder, is characterized by progressive neuronal loss, especially in the hippocampus and cortex [1]. The two main histopathological hallmarks of AD are the accumulation of extracellular neuritic plaques, containing amyloid-β (Aβ), and of neurofibrillary tangles, consisting mainly of hyperphosphorylated forms of the microtubule-associated protein tau [1]. Most AD patients are sporadic (SAD), but three genes have been associated with the familial form (FAD): amyloid-β protein precursor (AβPP), presenilin-1 (PS1), and presenilin-2 (PS2). Clinically, FAD is similar to SAD but has earlier onset. Presenilins are components of the γ-secretase complex (also containing APH1, nicastrin, and PEN2) that, together with β-secretase, processes AβPP to produce Aβ [1]. In the mainstream view, both SAD and FAD arise when AβPP is processed to Aβ, which accumulates in extracellular plaques. Aβ is toxic to cells and the resulting stress promotes tau hyperphosphorylation, leading to the tangles. The overall process has been called the "amyloid cascade" hypothesis [2,3]. This hypothesis reconciles findings from different approaches to the disease and has served as the basis for many key experiments in vivo and in vitro. However, certain questions that are central to understanding the pathogenesis of AD and the processing of Aβ remain unsolved.The first question concerns features of AD that are not obviously linked to plaque or tangle formation. While plaques and tangles are hallmarks of the disease, other apparently unrelated laboratory abnormali-

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Brain Inflammation, Cholesterol, and Glutamate as Interconnected Participants in the Pathology of Alzheimers Disease

Cited by 25 publications

References 294 publications

HIV-tat induces formation of an LRP–PSD-95– NMDAR–nNOS complex that promotes apoptosis in neurons and astrocytes

HIV-tat induces formation of an LRP–PSD-95– NMDAR–nNOS complex that promotes apoptosis in neurons and astrocytes

Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria

Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

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