Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity.

Tau-mediated toxicity is associated with cognitive decline and Alzheimer's disease (AD) progression. In particular, tau post-translational modifications (PTMs) are thought to generate aberrant tau species resulting in neuronal dysfunction. Despite being well characterized in postmortem AD brain, it is unclear how caspase-mediated C-terminal tau cleavage promotes neurodegeneration, as few studies have developed the models to dissect this pathogenic mechanism. Here, we show that proteasome impairment results in cleaved tau accumulation at the post-synaptic density (PSD), a process that is modulated by neuronal activity. Cleaved tau (at residue D421) impairs neuronal firing and causes inefficient initiation of network bursts, consistent with reduced excitatory drive. We propose that reduced neuronal activity, or silencing, is coupled to proteasome dysfunction, which drives cleaved tau accumulation at the PSD and subsequent synaptotoxicity. Our study connects three common themes in the progression of AD: impaired proteostasis, caspase-mediated tau cleavage, and synapse degeneration.

Methylphenidate Reversal of Executive Dysfunction in a Patient with Bi-Frontal Lobe Glioblastoma.

An elderly man with advanced glioblastoma developed neuro-cognitive deficits that were reversed by methylphenidate. After tumor resection from the right frontal lobe, he received cranial irradiation, temozolomide and Tumor Treating Fields (TTFields). MRI afterwards showed enhancements near the resection cavity and the contralateral frontal lobe. The patient experienced mild executive dysfunction that was not limiting his activities. Adjuvant temozolomide was started along with TTFields. After 2 cycles, his brain MRI showed stable disease, but he exhibited significant executive dysfunction. Methylphenidate improved his neuro-cognitive slowing in cycles 3 and 4. His disease eventually progressed during the 5th cycle, and he experienced a marked decline in activities. Repeat head MRI revealed tumor progression and cerebral edema. Treatments were discontinued while dexamethasone improved his neurological functions and bevacizumab biosimilar was later added. This case demonstrates the activity of methylphenidate for managing executive dysfunction in patients with glioblastoma while minimizing the use of dexamethasone.