Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Caldwell, Charles C.; Yao, Jia; Brinton, Roberta Dı́az

doi:10.1007/s13311-014-0324-8

Cited by 67 publications

(47 citation statements)

References 197 publications

(275 reference statements)

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“…Rivastigmine is prescribed to treat mild-to-moderate dementia. The consensus of the field is that such stages may be too late to apply disease-modifying treatments [24][25][26] . We contend, in agreement with this trend, that any diseasemodifying outcomes associated with rivastigmine have been effectively hidden by the disease stages in which the drug is typically prescribed.…”

Section: Introductionmentioning

confidence: 99%

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

et al. 2020

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Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases-Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the nonamyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.

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Section: Introductionmentioning

confidence: 99%

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

et al. 2020

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“…Alzheimer's disease is thought to develop over decades [39][40][41]. However, detailed molecular studies of AD brains can only be based on post-mortem tissues.…”

Section: Age-dependent Disruption Of Ire-driven Iron Homeostasis In Tmentioning

confidence: 99%

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Hin

Newman

Pederson

et al. 2020

Preprint

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Background: Iron trafficking and accumulation has been associated with Alzheimer's disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterised, making it difficult to explore these in existing datasets. Results: We identified sets of genes predicted to contain Iron Responsive Elements (IREs), and used these to explore iron dyshomeostasis responses in transcript datasets involving (1) cultured cells under iron overload and deficiency treatments, (2) post-mortem brain tissues from AD and other neuropathologies, (3) 5XFAD transgenic mice modelling AD pathologies, and (4) a zebrafish knock-in model of early-onset, familial AD (fAD). IRE gene sets were sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, we see changes in 3' IRE transcript abundance as amongst the earliest observable in zebrafish fAD-like brains and preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some 3' IRE transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead show decreased stability, indicating that this is not a generalizable paradigm. Conclusions: Our results reveal iron dyshomeostasis as a likely early driver of fAD and as able to distinguish AD from other brain pathologies. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis responses in different species, tissues, and conditions.

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“…While emphasis is increasingly shifting to early intervention [2, 54], approved treatments for those with early memory loss, including those with SCD [18, 55, 56], are lacking. Moreover, although memory complaints have been consistently associated with adverse psychosocial outcomes and poor perceived health, those with SCD rarely seek care for their symptoms [24].…”

Section: Introductionmentioning

confidence: 99%

Effects of Meditation versus Music Listening on Perceived Stress, Mood, Sleep, and Quality of Life in Adults with Early Memory Loss: A Pilot Randomized Controlled Trial

Innes

Selfe

Khalsa

et al. 2016

JAD

101

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Background Older adults with subjective cognitive decline (SCD) are at increased risk not only for Alzheimer’s disease, but for poor mental health, impaired sleep, and diminished quality of life (QOL), which in turn, contribute to further cognitive decline, highlighting the need for early intervention. Objective In this randomized controlled trial, we assessed the effects of two 12-week relaxation programs, Kirtan Kriya Meditation (KK) and music listening (ML), on perceived stress, sleep, mood, and health-related QOL in older adults with SCD. Methods Sixty community-dwelling older adults with SCD were randomized to a KK or ML program and asked to practice 12 minutes daily for 12 weeks, then at their discretion for the following 3 months. At baseline, 12 weeks, and 26 weeks, perceived stress, mood, psychological well-being, sleep quality, and health-related QOL were measured using well-validated instruments. Results Fifty-three participants (88%) completed the 6-month study. Participants in both groups showed significant improvement at 12 weeks in psychological well-being and in multiple domains of mood and sleep quality (p’s ≤ 0.05). Relative to ML, those assigned to KK showed greater gains in perceived stress, mood, psychological well-being, and QOL-Mental Health (p’s ≤ 0.09). Observed gains were sustained or improved at 6 months, with both groups showing marked and significant improvement in all outcomes. Changes were unrelated to treatment expectancies. Conclusions Findings suggest that practice of a simple meditation or ML program may improve stress, mood, well-being, sleep, and QOL in adults with SCD, with benefits sustained at 6 months and gains that were particularly pronounced in the KK group.

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Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Cited by 67 publications

References 197 publications

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Effects of Meditation versus Music Listening on Perceived Stress, Mood, Sleep, and Quality of Life in Adults with Early Memory Loss: A Pilot Randomized Controlled Trial

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