Colom-Cadena, M. | Search bioRxiv

bioRxiv2021

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

Synapse loss is associated with cognitive decline in Alzheimers disease (AD) and owing to their plastic nature, synapses are an ideal target for therapeutic intervention. Oligomeric amyloid beta (A{beta}) 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 A{beta} 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 A{beta}-mediated neurotoxicity. Here, we tested whether this channel could also be involved in A{beta} 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 Alzheimers disease derived brain homogenate. These results suggest that approaches to reduce Kv3.4 expression and/or function could be protective against A{beta}-induced synaptic alterations.

neuroscience↗

bioRxiv2021

TMEM97 increases in synapses and is a potential synaptic Aβ binding partner in human Alzheimer's disease

Synapse loss correlates with cognitive decline in Alzheimers disease, and soluble oligomeric amyloid beta is implicated in synaptic dysfunction and loss. An important knowledge gap is the lack of understanding of how amyloid beta leads to synapse degeneration. In particular, there has been difficulty in determining whether there is a synaptic receptor that binds amyloid beta and mediates toxicity. While many candidates have been observed in model systems, their relevance to human AD brain remains unknown. This is in part due to methodological limitations preventing visualization of amyloid beta binding at individual synapses. To overcome this limitation, we combined two high resolution microscopy techniques: array tomography and Forster resonance energy transfer (FRET) to image over 1 million individual synaptic terminals in temporal cortex from AD (n=9) and age matched control cases (n=6). Within postsynaptic densities, amyloid beta generates a FRET signal with transmembrane protein 97, cellular prion protein, and postsynaptic density 95. Transmembrane protein 97 is also present in a higher proportion of postsynapses in Alzheimers brain compared to controls. Further, we inhibited amyloid beta / transmembrane protein 97 interaction in a mouse model of amyloidopathy by treating with the an allosteric modulator CT1812 or vehicle. CT1812 drug concentration correlated negatively with synaptic FRET signal between transmembrane protein 97 and amyloid beta. In human induced pluripotent stem cell derived neurons challenged with human Alzheimers brain homogenate, transmembrane protein 97 and amyloid beta are present in synapses. Transcriptional changes are induced by A{beta} including changes in genes involved in neurodegeneration and neuroinflammation. CT1812 treatment of these neurons caused changes in gene sets involved in synaptic function. These data support a role for transmembrane protein 97 in the synaptic binding of amyloid beta in human Alzheimers disease brain where it may mediate synaptotoxicity.

neuroscience↗