Revealing Beta Amyloid Mechanisms of Action in Alzheimer's Disease
Olga Prikhodko, Ronald Freund, Emily Sullivan, Matthew Kennedy, and Mark Dell’Acqua
(see article e0675242024)
Beta amyloid buildup is a primary mediator of Alzheimer's disease (AD) pathology. Thus, insight into the mechanisms through which it disrupts synaptic activity and contributes to cell death is invaluable. In this issue, Prikhodko et al. discovered how beta amyloid causes glutamatergic NMDA receptor dysfunction and drives dendritic spine loss. Building off previous studies demonstrating that calcineurin signaling contributes to beta amyloid toxicity, the authors used a genetic line of mice to probe the role of a scaffolding protein for calcineurin, A-kinase-anchoring protein (AKAP) 150, in the synaptic effects of beta amyloid toxicity. They found that local postsynaptic AKAP150-calcineurin signaling was required for NMDA receptor impairment and dendritic spine loss. They also found that beta amyloid acutely interacted with this signaling system by activating metabotropic glutamate receptor 1 (mGluR1). This interaction led to dephosphorylation of NMDA receptor subunits and destabilized dendritic spines. This study provides detailed mechanistic clarity into how exactly beta amyloid impairs the functioning of glutamatergic synapses and triggers synapse loss. The identification of several receptors and proteins involved may inform the development of new therapeutics for AD.
Spine density was unchanged in a genetic AKAP150 knock-in mouse following exposure to vehicle or varying beta amyloid oligomer concentrations. This was not the case in wild-type controls (not pictured). See Prikhodko et al. for more information.
Extending Language Dysfunction Research into a Non-European Population
Kangrun Wang, Fangfang Xie, Chaorong Liu, Ge Wang, Min Zhang et al.
(see article e0558242024)
Existing knowledge on language dysfunction in epilepsy is centered on European languages. Wang et al. addressed this oversight in their study by investigating Chinese language dysfunction in temporal lobe epilepsy (TLE). They examined Chinese verbal fluency in nearly 60 patients with TLE and in 29 controls without TLE while assessing neural associations with language function using functional magnetic resonance imaging. Activation/deactivation maps, functional connectivity, degree centrality, and community features of frontal and temporal regions were compared. The authors discovered impaired verbal fluency scores in the TLE patient population and identified the left anterior inferior temporal gyrus as important for Chinese fluency. Prior to this work, verbal fluency-related functions of this structure were largely unknown, and it has not been thoroughly studied in neuropsychological diseases. Future work may look at the clinical relevance of targeting this brain region to improve language dysfunction in Chinese patients with left TLE. This study emphasizes the need for better representation of non-European languages in studies evaluating the neural representation of language and language deficit in disease.
Footnotes
This Week in The Journal was written by Paige McKeon
