P1‐473: Aβ disrupts spinodendritic calcium regulation <i>in vivo</i>

Kuchibhotla, Kishore V.; Goldman, Samuel T.; Lattarulo, Carli; Hyman, Bradley T.; Bacskai, Brian J.

doi:10.1016/j.jalz.2008.05.1056

Cited by 1 publication

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“…to enter the parent dendrite that causes a loss of spineto-dendrite Ca 2+ homeostasis, as observed through Ca 2+ imaging in APP/PS1 mice (Kuchibhotla et al, 2008). Our observation that K v 3.4 knockdown shifts spine morphology from stubby to thin in APP/PS1 mice is interesting as thin spines become less prevalent alongside age-related cognitive deterioration in monkeys (Dumitriu et al, 2010).…”

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confidence: 57%

Reducing voltage-dependent potassium channel Kv3.4 levels ameliorates synapse loss in a mouse model of Alzheimer’s disease

Yeap

Sathyaprakash²,

Toombs³

et al. 2021

Preprint

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Synapse loss is associated with cognitive decline in Alzheimer’s disease (AD) and owing to their plastic nature, synapses are an ideal target for therapeutic intervention. Oligomeric amyloid beta (Aβ) around amyloid plaques is known to contribute to synapse loss in mouse models and is associated with synapse loss in human AD brain tissue, but the mechanisms leading from Aβ to synapse loss remain unclear. Recent data suggest that the fast-activating and -inactivating voltagegated potassium channel subtype 3.4 (Kv3.4) may play a role in Aβ-mediated neurotoxicity. Here, we tested whether this channel could also be involved in Aβ synaptotoxicity. Using adeno-associated virus and CRISPR (clustered regularly interspaced short palindromic repeats) technology, we reduced Kv3.4 expression in neurons of the somatosensory cortex of APP/PS1 mice. These mice express human familial AD associated mutations in amyloid precursor protein and presenilin 1 and develop amyloid plaques and plaque-associated synapse loss similar to that observed in AD brain. We observe that reducing Kv3.4 levels ameliorates dendritic spine loss and changes spine morphology compared to control virus. In support of translational relevance, Kv3.4 protein was observed in human AD and control brain and is associated with synapses in human iPSC-derived cortical neurons. Interestingly, we observe a decrease in Kv3.4 expression in iPSC derived cortical neurons when they are challenged with human Alzheimer’s disease derived brain homogenate. These results suggest that approaches to reduce Kv3.4 expression and/or function could be protective against Aβ-induced synaptic alterations.

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Section: +mentioning

confidence: 57%