Preserved neurogenesis in non-demented individuals with AD neuropathology

Briley, David; Ghirardi, Valeria; Woltjer, Randy; Renck, Alicia; Zolochevska, Olga; Taglialatela, Giulio; Micci, Maria Adelaide

doi:10.1038/srep27812

Cited by 65 publications

(74 citation statements)

References 33 publications

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“…Interestingly, eleven proteins from our dataset cluster into the nervous system development and function pathway. This is consistent with our previous findings showing that when compared to AD and MCI, NDAN individuals have higher rate of neurogenesis in the dentate gyrus, which is positively correlated to their ability to escape (or significantly delay) dementia [51]. …”

Section: Resultssupporting

confidence: 93%

“…UCHL1 is expressed mostly by neurons and neuroendocrine cells, and it was found in Lewy bodies [122] and NFTs [123]. Interestingly, Lombardino et al showed that replaceable neurons have lower levels of UCHL1 when compared to non-replaceable neurons [124], which can be in concordance with the increased neurogenesis in NDAN [51] one of the hypothesis behind NDAN preserved cognitive function.…”

Section: Discussionmentioning

confidence: 95%

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Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Zolochevska

Bjorklund

Woltjer

et al. 2018

JAD

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Some individuals, here referred to as Non-Demented with Alzheimer’s Neuropathology (NDAN), retain their cognitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer’s disease (AD). In NDAN, unlike AD, toxic amyloid-β oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid-β in NDAN may thus enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanism(s) responsible for this resistance remains unresolved and understanding such protective biological processes could reveal novel targets for the development of effective treatments for AD. The present study uses a proteomic approach to compare the hippocampal postsynaptic densities of NDAN, AD, and healthy age-matched persons to identify protein signatures characteristic for these groups. Subcellular fractionation followed by 2D gel electrophoresis and mass spectrometry were used to analyze the PSDs. We describe fifteen proteins which comprise the unique proteomic signature of NDAN PSDs, thus setting them apart from control subjects and AD patients.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 95%

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Zolochevska

Bjorklund

Woltjer

et al. 2018

JAD

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“…In particular, older adults with high levels of exposure to particulate air pollution show poorer cognitive outcomes than non-exposed individuals (Ailshire and Clarke 2015). Aberrant neurogenesis is associated with poor cognitive functioning, and even individuals having characteristic AD neuropathology show no impairment of cognitive functions when neurogenesis is conserved (Briley et al 2016). These considerations should, however, be tempered by the fact that in the present study, the persistence over time of the effect of DE on neurogenesis was not assessed and that an assessment of cognitive behavior was not carried out.…”

Section: Discussionmentioning

confidence: 99%

Acute exposure to diesel exhaust impairs adult neurogenesis in mice: prominence in males and protective effect of pioglitazone

et al. 2018

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Adult neurogenesis is the process by which neural stem cells give rise to new functional neurons in specific regions of the adult brain, a process that occurs throughout life. Significantly, neurodegenerative and psychiatric disorders present suppressed neurogenesis, activated microglia, and neuroinflammation. Traffic-related air pollution has been shown to adversely affect the central nervous system. As the cardinal effects of air pollution exposure are microglial activation, and ensuing oxidative stress and neuroinflammation, we investigated whether acute exposures to diesel exhaust (DE) would inhibit adult neurogenesis in mice. Mice were exposed for 6 h to DE at a PM concentration of 250-300 μg/m, followed by assessment of adult neurogenesis in the hippocampal subgranular zone (SGZ), the subventricular zone (SVZ), and olfactory bulb (OB). DE impaired cellular proliferation in the SGZ and SVZ in males, but not females. DE reduced adult neurogenesis, with male mice showing fewer new neurons in the SGZ, SVZ, and OB, and females showing fewer new neurons only in the OB. To assess whether blocking microglial activation protected against DE-induced suppression of adult hippocampal neurogenesis, male mice were pre-treated with pioglitazone (PGZ) prior to DE exposure. The effects of DE exposure on microglia, as well as neuroinflammation and oxidative stress, were reduced by PGZ. PGZ also antagonized DE-induced suppression of neurogenesis in the SGZ. These results suggest that DE exposure impairs adult neurogenesis in a sex-dependent manner, by a mechanism likely to involve microglia activation and neuroinflammation.

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“…An examination of the postsynaptic proteome of such NDAN individuals provides some veracity to this hypothesis identifying a unique proteomic signature for the NDAN postsynaptic densities (Zolochevska, Bjorklund, Woltjer, Wiktorowicz, & Taglialatela, ). Enhanced neurogenesis may also play a part, and these dementia‐resistant subjects also show an increased number of neural stem cells and new neurons in the hippocampal dentate gyrus as well as a unique expression of neurogenesis‐regulating miRNAs (Briley et al, ). These observations in themselves may provide new neuroprotective strategies and therapeutic targets in the search for novel treatments for AD.…”

Section: Pathways To Amyloid Its Clearance and Neuronal Toxicitymentioning

confidence: 99%

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Nalivaeva

Turner

2019

British J Pharmacology

135

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Targeting the amyloid‐β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β‐ and γ‐secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid‐degrading enzymes (ADEs) and by a variety of transport processes. The development of late‐onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin‐degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up‐regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Preserved neurogenesis in non-demented individuals with AD neuropathology

Cited by 65 publications

References 33 publications

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Acute exposure to diesel exhaust impairs adult neurogenesis in mice: prominence in males and protective effect of pioglitazone

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

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