Systemic immune system alterations in early stages of Alzheimer's disease

Zhang, Rongzhen; Miller, Robert G.; Madison, Catherine; Jin, Xia; Honrada, Ronald; Harris, Will; Katz, Jonathan; Forshew, Dallas; McGrath, Michael S.

doi:10.1016/j.jneuroim.2013.01.002

Cited by 98 publications

(63 citation statements)

References 65 publications

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“…Another study found that a panel of serum proteins has diagnostic value 161 , although the sensitivity and specificity of this test need improvement. Individual blood proteins, including biomarkers of neurodegeneration (such as neurofilament light protein, neuron-specific enolase and heart fatty acid binding protein) and glial activation biomarkers (such as YKL-40 and monocyte chemotactic protein 1) also exhibit potential for AD diagnosis and prognostication [162][163][164][165] . Leukocyte surface protein phenotyping and functional phenotyping might also prove useful; leukocyte surface expression of P2X7 is decreased in patients with AD and is linked to altered phagocytic function of monocytes 45 .…”

Section: Blood Proteinsmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Blood Proteinsmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…A meta-analysis of forty studies in which peripheral blood cytokine concentrations reveal that AD is accompanied by higher peripheral concentrations of IL-6, TNF-α, IL-1β, TGF-β, IL-12, and IL-8 [102]. Activation of circulating peripheral immune cells is observed in patients with early stages of AD [103]. Several studies have also reported the correlation between peripheral inflammation and cognitive dysfunction.…”

Section: Peripheral and Central Inflammation Connectionmentioning

confidence: 99%

Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease

Pugazhenthi¹,

Qin²,

Reddy³

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

466

306

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Cognitive decline in chronic diabetic patients is a less investigated topic. Diabetes and obesity are among the modifiable risk factors for Alzheimer's disease (AD), the most common form of dementia. Studies have identified several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, and inflammation that are observed in these disorders. Advanced glycation end products generated by chronic hyperglycemia and their receptor RAGE provide critical links between diabetes and AD. Peripheral inflammation observed in obesity leads to insulin resistance and type 2 diabetes. Although the brain is an immune-previleged organ, crosstalks between peripheral and central inflammation have been reported. Damage to the blood brain barrier (BBB) as seen with aging can lead to infiltration of immune cells into the brain, leading to the exacerbation of central inflammation.Neuroinflammation, which has emerged as an important cause of cognitive dysfunction, could provide a central mechanism for aging-associated ailments. To further add to these injuries, adult neurogenesis that provides neuronal plasticity is also impaired in the diabetic brain. This review discusses these molecular mechanisms that link obesity, diabetes and AD.

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“…Links between Alzheimer’s disease and local or systemic immunologic dysfunction have previously been described [29–31]. The immune mechanisms and microglia are shown to be involved in the clearance of amyloid beta peptide [32].…”

Section: Resultsmentioning

confidence: 99%

Extensive Association of Common Disease Variants with Regulatory Sequence

et al. 2016

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Overlap between non-coding DNA regulatory sequences and common variant associations can help to identify specific cell and tissue types that are relevant for particular diseases. In a systematic manner, we analyzed variants from 94 genome-wide association studies (reporting at least 12 loci at p<5x10-8) by projecting them onto 466 epigenetic datasets (characterizing DNase I hypersensitive sites; DHSs) derived from various adult and fetal tissue samples and cell lines including many biological replicates. We were able to confirm many expected associations, such as the involvement of specific immune cell types in immune-related diseases and tissue types in diseases that affect specific organs, for example, inflammatory bowel disease and coronary artery disease. Other notable associations include adrenal glands in coronary artery disease, the immune system in Alzheimer’s disease, and the kidney for bone marrow density. The association signals for some GWAS (for example, myopia or age at menarche) did not show a clear pattern with any of the cell or tissue types studied. In general, the identified variants from GWAS tend to be located outside coding regions. Altogether, we have performed an extensive characterization of GWAS signals in relation to cell and tissue-specific DHSs, demonstrating a key role for regulatory mechanisms in common diseases and complex traits.

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Systemic immune system alterations in early stages of Alzheimer's disease

Cited by 98 publications

References 65 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease

Extensive Association of Common Disease Variants with Regulatory Sequence

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