Activation of the Neuronal Cell Cycle in Brains in Amnestic Mild Cognitive Impairment: Early Involvement in the Progression of Alzheimer’s Disease

Abstract

Activation of cell-cycle machinery in Alzheimer’s disease (AD) brain was reported by Mark Smith and colleagues and by other researchers. Among other biochemical processes underlying this activation, the notion that AD brain, under the onslaught of oxidative and nitrosative damage leading to neuronal loss, neurons would attempt to replenish their numbers by entering the cell cycle. However, being post-mitotic, neurons entering the cell cycle would become trapped therein, ultimately leading to death of these neurons. Yang and co-workers and the Butterfield laboratory first reported that similar activation of the cell cycle was present in the brains of individuals with amnestic mild cognitive impairment (MCI), arguably the earliest clinical stage of AD, but who demonstrate normal activities of daily living and no dementia. Activation of the cell cycle in MCI brain is consonant with the concept that this process is an early aspect in the progression of AD. This brief review article discusses these findings and recognizes the contribution of Dr. Mark Smith to the investigation of cell-cycle activation in AD brain and other aspects of AD neuropathology.

Keywords

Alzheimer’s disease cell-cycle activation mild cognitive impairment oxidative damage Pin1

INTRODUCTION

Arguably, the earliest stage of clinical manifestations of Alzheimer’s disease (AD) is amnestic mild cognitive impairment (MCI). 1 In both conditions, oxidative damage to brain is rampant, and redox proteomics identified numerous proteins and key metabolic pathways that were oxidatively modified and consequently dysfunctional, leading to neuronal death.2 –8

In AD brains, evidence of an activation of the cell cycle brain was reported by Mark Smith and colleagues9 –12 and from other laboratories.13 –16 Because neurons are post-mitotic cells, activation of the cell cycle in neurons leads to their being trapped within the cell cycle with no other option than undergoing cell death, with evidence of apoptosis present.

Following the Mark Smith insights into cell-cycle activation and consequent neuronal loss in AD brains, Yang and co-workers 17 and the Butterfield laboratory18,19, 18,19 used immunochemical methods to describe elevation of cell cycle related-proteins in MCI brains to address the question of whether neuronal cell-cycle activation would be an early process in the progression of AD.

Moreover, the cell-cycle protein machinery is regulated by several factors, one of which is the action of the peptidyl-prolyl cis-trans isomerase protein (Pin1).20,21, 20,21 Pin1 is a regulatory protein that binds to phosphorylated Ser/Thr residues on the N-terminal side of a Pro residue.20 –24 The proline residue of the p-Ser/Thr-Pro motif of the Pin1 target protein is converted by Pin1 from the cis to trans conformation and vice versa, thereby significantly changing the conformation, and therefore regulating the function, of the target protein to which Pin1 is bound.

This brief review article provides a response to the question posed above about whether the MCI brain demonstrates evidence for cell-cycle activation.

EVIDENCE FOR AND IMPLICATIONS OF CELL-CYCLE ACTIVATION IN MCI BRAINS

As noted above, cell-cycle activation in AD brains with implications for neuronal death was reported by Mark Smith and colleagues.9 –12 Yang, Mufson, and Herrup used immunohistochemistry to describe elevation of cell cycle related-proteins cyclin D, cyclin B, and proliferating cell nuclear antigen in hippocampus and entorhinal cortex and basal nucleus of Mynert in MCI and AD brains relative to brains from individuals without loss of cognition. 17 The Butterfield laboratory using immunochemistry analyses of hippocampus and inferior parietal lobule also reported elevation of the cell-cycle related proteins, cyclin-dependent kinase-2 (CDK2), cyclin-dependent kinase-5 (CDK5), and cyclin G1 in MCI brains compared to aged-matched controls, consonant with the concept that neuronal cell-cycle activation occurred in MCI brain and therefore would be an early process in the progression of AD.18,19, 18,19 The congruence of these two studies noted above strongly supports this latter statement.

Another, but related, mechanism by which cell-cycle activation occurs in MCI and AD brains proteins conceivably could be related to dysregulation of some of these proteins by oxidation of and diminished function in the regulatory protein, Pin1. As noted above, Pin1 normally regulates the activity of key proteins involved in the cell cycle.18 –24

The amyloid-β protein precursor (AβPP), from which the neurotoxic 42-amino acid amyloid-β peptide (Aβ₄₂) is formed, and phosphorylation and dephosphorylation processes of the microtubule assembly stabilizing-protein tau are target proteins regulated by Pin1.10,11, 10,11 Therefore, two of the major hallmarks of AD neuropathology, neuritic (senile) plaques, composed of fibrillar Aβ₄₂ and Aβ₄₀ surrounded by dystrophic neurites and other moieties, and neurofibrillary tangles, composed of aggregated hyperphosphorylated tau, are directly associated with the action of the regulatory protein Pin1. Moreover, hyperphosphorylated tau is known to fall off microtubules, leading to disassembly of the latter with consequent loss of the tracks on which cargo proteins transport mitochondria and other trophic moieties to the presynaptic terminus and therefore to synaptic starvation of ATP. Of course, this would lead to significant damage to synapse-facilitated neurotransmission and cognitive loss.

The Butterfield laboratory first reported that, in AD and MCI brains, levels of Pin1 are decreased and that this regulatory protein is oxidatively damaged and dysfunctional in both conditions, consistent with the notion that Pin1-regulated proteins are no longer regulated nor capable of being changed in conformation secondary to proline cis-trans isomerism.21,23–25 , 21,23–25 Relevant to MCI and AD brains, if AβPP is trapped in the proline cis-isomeric conformation due to oxidatively dysfunctional Pin1, the amyloidogenic processing of APP would be enhanced, i.e., neurotoxic Aβ₄₂ will be formed. 26 Small oligomers of Aβ₄₂ are known to lead to synaptic dysfunction27,28, 27,28 and to neuronal death. 2 Similarly, in MCI and AD brains if in the tau kinase, glycogen synthase kinase-3β (GSK-3β), or in the tau phosphatase, protein phosphatase 2A (PP2A), the respective prolines are trapped in the cis-isomeric conformation, then oxidatively dysfunctional Pin1 would no longer regulate proteins involved in the phosphorylation and dephosphorylation of tau, i.e., promotion of neurofibrillary tangle formation would be enhanced. 29 These latter aggregates are known to promote neuronaldeath. 30

The oxidative modification and subsequent dysfunction of Pin1 in AD and MCI brains24,25,31 , 24,25,31 and its proposed role in cell-cycle activation18,19, 18,19 reported from our laboratory is consistent with research reported by Mark Smith and colleagues on the intersection of oxidative stress, tau phosphorylation, and cell-cycle-related phenomena associated with activation of p38 kinase. 12

ON THE 100TH VOLUME OF THE JOURNAL OF ALZHEIMER’S DISEASE AND COMMENTARY ON MARK SMITH RELEVANT TO HIS CONTRIBUTION TO CELL-CYCLE RESEARCH IN AD

The current author wishes to congratulate the Editors of the Journal of Alzheimer’s Disease (JAD), particularly the able leadership of Founding Editor and Editor-in-Chief, Dr. George Perry (assisted in the beginning by Dr. Mark Smith until his untimely death and now by Dr. Paula Moreira as Co-Editor-in-Chief), on this landmark achievement of publishing the 100th volume of JAD. My first publication in JAD was in volume 2 in which confirmatory results that Aβ added to primary neuronal cultures led to significant reactive oxygen species production and oxidative stress-mediated neuronal death, and that vitamin E, a chain-breaking antioxidant, markedly reduced these effects. 32 Since the mechanism of lipid peroxidation involves a chain reaction, and small oligomers of Aβ are highly soluble in lipid bilayers,2,33, 2,33 these results supported our laboratory’s results that demonstrated lipid peroxidation involving Aβ₄₂ both in vitro in primary neuronal cultures and rodent synaptosomal membranes and in vivo in AD and MCI brains.2,6,7,33 , 2,6,7,33 I wish for continued success for JAD.

Regarding Dr. Mark Smith, to whose memory and legacy this supplement to the 100th volume of JAD is dedicated: Mark Smith was a prodigious researcher, who employed methods of pathology, particularly immunohistochemistry, to delve into neuropathological alterations in AD brains. Dr. Smith, often in collaboration with Dr. George Perry, reported numerous findings consistent with oxidative stress being critical for the biochemical underpinnings of the clinical presentations of this devastating dementing disorder.34,35, 34,35 Among these many findings in AD brain were indications of oxidative and nitrosative alterations associated with Aβ₄₂ oligomers34 –36 and activation of the cell cycle machinery.9 –12 Later research from Smith still emphasized oxidative stress as an underlying aspect of AD, but he de-emphasized the role of Aβ in these findings. 37 In contrast to the latter, two important findings stand out: first, substitution of the key methionine residue 35 of Aβ₄₂ by leucine in an AD mouse model showed no elevated oxidative damage in brain relative to unaffected littermates and in contradistinction to the significantly elevated oxidative stress in brain in the AD mouse model brain in which the key Met residue of Aβ₄₂ was present; 38 and second finding is the recently approved AD therapeutic agent, lecanemab (Leqembi), the only FDA-approved agent that is disease-modifying in AD, works by targeting Aβ₄₂ oligomers. 39 Leqembi also is associated with troubling problems, most notably brain bleeding in a significant percentage of patients. These two findings support the concept that Aβ₄₂ oligomers are associated with oxidative stress and Leqembi is the first in a hopefully increasing number of promising therapeutic agents for AD that work by targeting Aβ₄₂ oligomers.

Small oligomers of Aβ₄₂ insert into lipid bilayers of neurons and are associated with synaptic dysfunction27,28, 27,28 and oxidative modification of lipids and proteins 2 that lead to cell death, from which cognitive decline would be a predicted outcome.

Dr. Mark Smith tragically died way too soon. His energy, passion and legacy of AD research continue to be missed.

AUTHOR CONTRIBUTIONS

D. Allan Butterfield (Conceptualization; Writing – original draft).

Footnotes

ACKNOWLEDGMENTS

The author thanks all his former graduate students and postdoctoral scholars who performed research associated with papers from the Butterfield laboratory cited in this current paper. The author also thanks the neuropathology faculty of the Sanders-Brown Center on Aging at the University of Kentucky for providing well-characterized brain specimens from AD, MCI, and non-cognitively affected individuals each with a very short post-mortem interval that were used in the studies cited in this brief review paper.

FUNDING

This paper was supported in part by funds from the Department of Chemistry of the University of Kentucky.

CONFLICT OF INTEREST

The author has no conflict of interest to report. The author is an Editorial Board member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer review.

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