Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

Marco, Luigi Yuri Di; Venneri, Annalena; Farkas, Eszter; Evans, Paul C.; Marzo, Alberto; Frangi, Alejandro F.

doi:10.1016/j.nbd.2015.08.014

Cited by 224 publications

(184 citation statements)

References 241 publications

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“…In addition, females appear to lose their cardiovascular protection after menopause and are at higher risk for cardiovascular disease [57,58]. Exercise has also been reported to be more effective in females in relation to cognitive decline [29] and may be more effective in the endothelial dysfunction in dementia [12], and the vascular form(s) of the condition [3]. There are also sex differences in obesity (females > males) with lithium responsive conditions such as bipolar diseases [59], as well as other mental illnesses [60].…”

Section: Discussionmentioning

confidence: 99%

“…In part, this may be due to disease heterogeneity [11], as some subsets may be more vascular-based in nature [12], while the basis for disease in others may reside in specific brain tissues such as the hippocampus [13]. Heterogeneity may also arise due to differences in inciting events versus events related to early and late disease, or possibly due to epigenetic alterations associated with a chronic disease.…”

Section: Introductionmentioning

confidence: 99%

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Would Adding Low Doses of Lithium Salts and/or Prebiotic Fibre Interventions to an Effective Exercise Protocol Further Enhance Retention of Cognitive Integrity? Potential for Preventing Loss of Cognition with Aging Using Combinations of Low Cost Regimens

Hart¹

2018

JBiSE

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It is clear that loss of cognition is becoming epidemic in our aging society. Onset of dementia and diseases such as Alzheimer's are very prevalent and the prognosis is not optimistic that numbers will decrease in the coming decades. Thus, this epidemic is impacting the quality of life of a large number of people, primarily females, as well as the health care systems of many countries. Of relevance is the fact that large clinical trials of candidate drugs to treat these conditions have not been overwhelming successes, indicating that we may need to take new directions or focus on prevention. One conservative approach in this regard has been the use of exercise protocols to both retain cognition and inhibit progression of loss. With the optimization of exercise protocols, it may be time to step back and ask "how can these successes be augmented to further inhibit risk and stabilize loss early in the development of these conditions?" An example of how this could be approached is via supplementation with low doses of minerals such as lithium salts, or supplementation of the diet with prebiotics in patients with obesity and metabolic syndrome. Regarding the former, recent epidemiological studies have indicated that the content of Li in the drinking water is associated with lower incidences of cognitive diseases/conditions. While not definitive, such clues may warrant performing controlled studies using low doses of lithium salts plus exer- cise to further optimize impact on retention of cognition in those at risk, or those with early disease. Similarly, patients with obesity are at higher risk to develop dementia, and prebiotics can correct some of the metabolic derangements associated with the microbiome in such patients to impact risk. Thus, multiple low cost interventions plus exercise could further enhance retention of cognitive integrity in specific populations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Would Adding Low Doses of Lithium Salts and/or Prebiotic Fibre Interventions to an Effective Exercise Protocol Further Enhance Retention of Cognitive Integrity? Potential for Preventing Loss of Cognition with Aging Using Combinations of Low Cost Regimens

Hart¹

2018

JBiSE

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“…PSEN fAD mutations that promote abnormal microvascular phenotypes may thereby predispose to, and accelerate the onset of, AD. (See also a recent comprehensive review of the role of vasculature in AD by Di Marco et al, [172]). …”

Section: What Then Of A␤pp A␤ and The A␤ 42 /A␤ 40 Ratio?mentioning

confidence: 99%

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

Jayne

Newman

Verdile

et al. 2016

JAD

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Abstract. The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESE-NILIN (PSEN) proteins is in ␥-secretase enzyme activity. One substrate of ␥-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A␤PP/APP) that is a fAD mutation locus. A␤PP is the source of the amyloid-␤ (A␤) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on ␥-secretase activity and A␤ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on ␥-secretase in AD. We then discuss the main ideas regarding the role of ␥-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and A␤PP) and look at alternative roles for A␤PP and A␤ in fAD. We present a case for an alternative interpretation of published data on the role of ␥-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN

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“…In addition, vascular degeneration and dysfunction is pathogenic and leads to neuronal degeneration in AD [17,18]. Although the potential hypoperfusion may contribute to secondary neuronal degeneration in PD [4], this study investigated whether the endothelial degeneration [3] is the cause or the result of neuronal degeneration by assessing the co-pathology of neuronal and vascular degeneration in the areas with a different extent of neuronal degeneration and PD pathology within the grey matter of the MFG, where there is no PD-related BBB leakage [4].…”

Section: Introductionmentioning

confidence: 99%

Endothelial Degeneration of Parkinson's Disease is Related to Alpha-Synuclein Aggregation

Yang¹,

Min²,

Mohammadi³

et al. 2017

J Alzheimers Dis Parkinsonism

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Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

Cited by 224 publications

References 241 publications

Would Adding Low Doses of Lithium Salts and/or Prebiotic Fibre Interventions to an Effective Exercise Protocol Further Enhance Retention of Cognitive Integrity? Potential for Preventing Loss of Cognition with Aging Using Combinations of Low Cost Regimens

Would Adding Low Doses of Lithium Salts and/or Prebiotic Fibre Interventions to an Effective Exercise Protocol Further Enhance Retention of Cognitive Integrity? Potential for Preventing Loss of Cognition with Aging Using Combinations of Low Cost Regimens

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

Endothelial Degeneration of Parkinson's Disease is Related to Alpha-Synuclein Aggregation

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