Browsing by Subject "Memory impairment"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    A serine protease KLK8 emerges as a regulator of regulators in memory: Microtubule protein dependent neuronal morphology and PKA-CREB signaling
    (Nature Publishing Group, 2018-07-02) Konar, Arpita; Kumar, Ashish; Maloney, Bryan; Lahiri, Debomoy K.; Thakur, Mahendra K.; Psychiatry, School of Medicine
    The multitude of molecular pathways underlying memory impairment in neurological disorders and aging-related disorders has been a major hurdle against therapeutic targeting. Over the years, neuronal growth promoting factors, intracellular kinases, and specific transcription factors, particularly cyclic AMP response element-binding protein (CREB), have emerged as crucial players of memory storage, and their disruption accompanies many cognitive disabilities. However, a molecular link that can influence these major players and can be a potential recovery target has been elusive. Recent reports suggest that extracellular cues at the synapses might evoke an intracellular signaling cascade and regulate memory function. Herein, we report novel function of an extracellular serine protease, kallikrein 8 (KLK8/Neuropsin) in regulating the expression of microtubule associated dendrite growth marker microtubule-associated protein (MAP2)c, dendrite architecture and protein kinase A (PKA)-CREB signaling. Both knockdown of KLK8 via siRNA transfection in mouse primary hippocampal neurons and via intra-hippocampal administration of KLK8 antisense oligonucleotides in vivo reduced expression of MAP2c, dendrite length, dendrite branching and spine density. The KLK8 mediated MAP2c deficiency in turn inactivated PKA and downstream transcription factor phosphorylated CREB (pCREB), leading to downregulation of memory-linked genes and consequent impaired memory consolidation. These findings revealed a protease associated novel pathway of memory impairment in which KLK8 may act as a "regulator of regulators", suggesting its exploration as an important therapeutic target of memory disorders.
  • Thumbnail Image
    Item
    Verbal fluency response times predict incident cognitive impairment
    (Alzheimer’s Association, 2022-04-06) Ayers, Matthew R.; Bushnell, Justin; Gao, Sujuan; Unverzagt, Frederick; Del Gaizo, John; Wadley, Virginia G.; Kennedy, Richard; Clark, David Glenn; Neurology, School of Medicine
    Introduction: In recent decades, researchers have defined novel methods for scoring verbal fluency tasks. In this work, we evaluate novel scores based on speed of word responses. Methods: We transcribed verbal fluency recordings from 641 cases of incident cognitive impairment (ICI) and matched controls, all participants in a large national epidemiological study. Timing measurements of utterances were used to calculate a speed score for each recording. Traditional raw and speed scores were entered into Cox proportional hazards (CPH) regression models predicting time to ICI. Results: Concordance of the CPH model with speed scores was 0.599, an improvement of 3.4% over a model with only raw scores and demographics. Scores with significant effects included animals raw and speed scores, and letter F speed score. Discussion: Novel verbal fluency scores based on response times could enable use of remotely administered fluency tasks for early detection of cognitive decline. Highlights: The current work evaluates prognostication with verbal fluency speed scores. These speed scores improve survival models predicting cognitive decline. Cases with progressive decline have some characteristics suggestive of Alzheimer's disease. The subset of acute decliners is probably pathologically heterogeneous.