Increased KIF11/kinesin-5 expression offsets Alzheimer Aβ-mediated toxicity and cognitive dysfunction

Lucero, Esteban; Freund, Ronald K.; Smith, Alexandra N.; Johnson, Noah R.; Dooling, Breanna; Sullivan, Elizabeth; Prikhodko, Olga; Ahmed, Md. Mahiuddin; Bennett, David A.; Hohman, Timothy J.; Dell’Acqua, Mark L.; Chial, Heidi J.; Potter, Huntington

doi:10.1016/j.isci.2022.105288

Cited by 8 publications

(6 citation statements)

References 88 publications

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“…This is supported by our findings that overexpression of Kin1 in kin3 mutant larvae, or Kin3 in kin1 mutant larvae rescued neuronal death, and that increasing either Kin1 or Kin3 levels compensate for some of the inhibitory effects of expressing Aβ 42Arc in Drosophila . This agrees with reports showing that increased KIF11 expression can improve cognitive performance of an AD mouse model 71 .…”

Section: Discussionsupporting

confidence: 93%

Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo

Francis,

Paonessa,

Fabre

et al. 2024

Preprint

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Alzheimers Disease is the leading cause of dementia and the most common neurodegenerative disorder. Understanding the molecular pathology of Alzheimers Disease may help identify new ways to reduce neuronal damage. In the past decades Drosophila has become a powerful tool in modelling mechanisms underlying human diseases. Here we investigate how the expression of the human 42-residue beta-amyloid (Abeta) carrying the E22G pathogenic Arctic mutation (Abeta42Arc) affects axonal health and behaviour of Drosophila. We find that Abeta42Arc flies present aberrant neurons, with altered axonal transport of mitochondrial and an increased number of terminal boutons at neuromuscular junctions. We demonstrate that the major axonal motor proteins kinesin-1 and kinesin-3 are essential for the correct development of neurons in Drosophila larvae and similar findings are replicated in human iPSC-derived cortical neurons. We then show that the over-expression of kinesin-1 or kinesin-3 restores the correct number of terminal boutons in Abeta42Arc expressing neurons and that this is associated with a rescue of the overall neuronal function, measured by negative geotaxis locomotor behavioural assay. We therefore provide new evidence in understanding the mechanisms of axonal transport defects in Alzheimers Disease, and our results indicate that kinesins should be considered as potential drug targets to help reduce dementia-associated disorders.

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Section: Discussionsupporting

confidence: 93%

Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo

Francis,

Paonessa,

Fabre

et al. 2024

Preprint

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“…Our hypothesis is bolstered by other studies showing that overexpression of a microtubule motor protein Kif11 improved cognition in 5XFAD mouse model while not changing Aβ load. 68…”

Section: Discussionmentioning

confidence: 99%

“…Our hypothesis is bolstered by other studies showing that overexpression of a microtubule motor protein Kif11 improved cognition in 5XFAD mouse model while not changing Aβ load. 68 To provide additional evidence of translatability of the resilience genes identified in the mouse, we cross-referenced our findings with a different human cohort of resilient individuals and/or data modality. Remarkably, we found corroborating evidence among many of the 61 mouse genes in human cohort transcriptional data sets, including predicted differential expression in resilience in multiple tissues (Table S4) and positive correlation with cognition (Table S5).…”

Section: Discussionmentioning

confidence: 99%

“…The immunohistochemistry study incorporated a different cohort of male and female 14-monthold AD-BXD mice from the following strains: 14,16,22,32,44,55,56,60,61,66,68,75,77,81,87,89,99,100, as well as the B6 and D2 F1s. For the female-only dataset, samples from the following AD-BXD strains were included: 14, 16, 22, 55, 75, 77, 81, 99, as well as the B6 and B6*D2 F1s.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Conserved cell-type specific signature of resilience to Alzheimer’s disease nominates role for excitatory intratelencephalic cortical neurons

Telpoukhovskaia

Hadad

Gurdon

et al. 2022

Preprint

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Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nuclear transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GABRB1, PTK2, and ROCK2. Nominated resilience genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Additionally, we identified several potential mechanisms of resilience, including regulation of membrane potential, axonal and dendritic growth, and general increase of protein cycle, potentially of membrane proteins. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

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“…In post-mitotic neurons, Kifs are essential motor proteins involved in neuronal migration, transport, and synaptic transmission (Joseph et al, 2021). Dysregulated expression of KIFs has been implicated in several neurological disorders, including amyotrophic lateral sclerosis, epilepsy, and Alzheimer’s disease (Asselin et al, 2020; Guillaud et al, 2020; Lucero et al, 2022). While the role of Kifs in neurons is well-established, their functions in NSPCs during embryonic brain development remain less explored.…”

Section: Introductionmentioning

confidence: 99%

Kinesin family member Kif23 regulates cytokinetic division and maintains neural stem/progenitor cell pool in the developing neocortex

Naher,

Kikkawa,

Iemura

et al. 2023

Preprint

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Accurate mitotic division of neural stem cell/progenitor cells (NSPCs) is crucial for the coordinated generation of progenitors and neurons in the developing cortex. Here, we investigated the pivotal role of Kif23, an N-kinesin motor protein, in embryonic mouse NSPCs. We found that Kif23 is highly expressed in the mitotic NSPCs within the embryonic cortex of both mouse and human. Knockdown (KD) of Kif23 led to precocious neurogenesis, attributed to an accelerated cell cycle exit, likely resulting from disrupted mitotic spindle orientation and impaired cytokinesis. Kif23 KD induced upregulation of the gamma-H2AX-p53-p21 signaling pathway, ultimately culminating in cytokinetic failure. Additionally, Kif23 depletion perturbed the apical surface structure of NSPCs and disrupted the proper localization of apical junctional proteins. Importantly, we demonstrated the successful rescue of Kif23 KD-induced phenotypes by introducing wild-type human KIF23, but not by a variant of KIF23 with a microcephaly-associated mutation. Our findings underscore the critical role of Kif23 in cortical development and provide novel insights into the intricate molecular mechanisms underlying pathogenesis of microcephaly.

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Increased KIF11/kinesin-5 expression offsets Alzheimer Aβ-mediated toxicity and cognitive dysfunction

Cited by 8 publications

References 88 publications

Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo

Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Aβ42 toxicity in vivo

Conserved cell-type specific signature of resilience to Alzheimer’s disease nominates role for excitatory intratelencephalic cortical neurons

Kinesin family member Kif23 regulates cytokinetic division and maintains neural stem/progenitor cell pool in the developing neocortex

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