An investigation into the role of P-glycoprotein in Alzheimer's disease lesion pathogenesis

Jeynes, Brian; Provias, John

doi:10.1016/j.neulet.2010.10.063

Cited by 52 publications

(42 citation statements)

References 27 publications

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“…This evidence suggests that accumulation of the toxic form of Aβ can lead to downregulation of the P-glycoprotein 1 transporter. This correlates with human studies that reported elevated levels of Aβ and decreases in P-glycoprotein 1 levels (233,234). The relative contributions to Aβ clearance from capillaries and astrocytes remains to be fully understood.…”

Section: Atp-binding Cassette Transporter Familysupporting

confidence: 87%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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Section: Atp-binding Cassette Transporter Familysupporting

confidence: 87%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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“…In 2011, Jeynes et al analyzed brain tissue of controls and AD patients. ABCB1 positive capillaries were inversely correlated with the presence of neurofibrillary tangles and senile plaques; again confirming our publication from 2004 (Jeynes and Provias, 2011; Vogelgesang et al, 2004). In 2011, our experimental work revealed a strong effect of ABCB1-deficiency in APPPS1 mice and in a mouse model of CAA (Krohn et al, 2011).…”

Section: Abc-transporters and Aβ – 13 Years Of Researchsupporting

confidence: 87%

Alzheimer’s and ABC transporters — new opportunities for diagnostics and treatment

Pahnke

Langer

Krohn

2014

Neurobiology of Disease

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Much has been said about the increasing number of demented patients and the main risk factor ‘age’. Frustratingly, we do not know the precise pattern and all modulating factors that provoke the pathologic changes in the brains of affected elderly. We have to diagnose early to be able to stop the progression of diseases that irreversibly destroy brain substance. Familiar AD cases have mislead some researchers for almost 20 years, which has unfortunately narrowed the scientific understanding and has, thus, lead to insufficient funding of independent approaches. Therefore, basic researchers hardly have been able to develop causative treatments and clinicians still do not have access to prognostic and early diagnostic tools. During the recent years it became clear that insufficient Aβ export, physiologically facilitated by the ABC transporter superfamily at the brain’s barriers, plays a fundamental role in disease initiation and progression. Furthermore, export mechanisms that are deficient in affected elderly are new targets for activation and, thus, treatment, but ideally also for prevention. In sporadic AD disturbed clearance of β-amyloid from the brain is so far the most important factor for its accumulation in the parenchyma and vessel walls. Here, we review findings about the contribution of ABC transporters and of the perivascular drainage/glymphatic system on β-amyloid clearance. We highlight their potential value for innovative early diagnostics using PET and describe recently described, effective ABC transporter-targeting agents as potential causative treatment for neurodegenerative proteopathies/dementias.

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“…In a Fischer 344/Brown-Norway (F344/BN) rat model of aging, both P-gp and LRP-1 expression were found to decrease with advancing age (Silverberg et al, 2010a). A reduction in P-gp levels has been correlated with increased amyloid burden and senile plaque development in AD (Cirrito et al, 2005;Jeynes and Provias, 2011). Age-related P-gp decrease in association with amyloid deposition is also seen in human aging (Vogelgesang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%