Amyloid-β (Aβ) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer’s disease (AD). Whereas in AD, Aβ is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aβ aggregated species, soluble oligomers are suggested to be responsible for most of Aβ’s toxic effects. Aβ oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aβ deposition and facilitate neurodegeneration, resulting in an Aβ-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aβ induces on synaptic dysfunction and network disorganization.

INTRODUCTION: For routine clinical implementation of Alzheimer's disease (AD) plasma biomarkers, fully automated random‐access platforms are crucial to ensure reproducible measurements. We aimed to perform an analytical validation and to establish cutoffs for AD plasma biomarkers measured with Lumipulse.METHODS: Two cohorts were included. UNIPG: n = 450 paired cerebrospinal fluid (CSF)/plasma samples from subjects along the AD‐continuum, subjects affected by other neurodegenerative diseases, and controls with known CSF profile; AMS: n = 40 plasma samples from AD and n = 40 controls. Plasma amyloid β (Aβ)42, Aβ40, and p‐tau181 were measured with Lumipulse. We evaluated analytical and diagnostic performance.RESULTS: Lumipulse assays showed high analytical performance. Plasma p‐tau181 levels accurately reflected CSF A+/T+ profile in AD‐dementia and mild cognitive impairment (MCI)‐AD, but not in asymptomatic‐AD. Plasma and CSF Aβ42/40 values were concordant across clinical AD stages. Cutoffs and probability‐based models performed satisfactorily in both cohorts.DISCUSSION: The identified cutoffs and probability‐based models represent a significant step toward plasma AD molecular diagnosis.

Loss-of-function mutations in the KCNA1 (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by KCNA1 mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation–induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a knock-in mouse model of EA1 and restored the neuromuscular transmission and climbing ability in Shaker (Kv1.1) mutant Drosophila melanogaster flies ( Sh ⁵ ). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.

Amyloid beta 1-42 (Aβ42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17β-estradiol is crucial for hippocampal LTP. We tested whether boosting the synthesis of neural-derived 17β-estradiol (nE2) saves hippocampal LTP by the neurotoxic action of Aβ42. Electrophysiological recordings were performed to measure dentate gyrus (DG) LTP in rat hippocampal slices. Using a pharmacological approach, we tested the ability of nE2 to counteract the LTP impairment caused by acute exposure to soluble Aβ42 aggregates. nE2 was found to be required for LTP in DG under physiological conditions. Blockade of steroid 5α-reductase with finasteride, by increasing nE2 synthesis from testosterone (T), completely recovered LTP in slices treated with soluble Aβ42 aggregates. Modulation of the glutamate N-methyl-D aspartate receptor (NMDAR) by memantine effectively rescued the LTP deficit observed in slices exposed to Aβ42, and memantine prevented LTP reduction observed under the blocking of nE2 synthesis. nE2 is able to counteract Aβ42-induced synaptic dysfunction. This effect depends on a rapid, non-genomic mechanism of action of nE2, which may share a common pathway with glutamate NMDAR signaling.

Aim: Calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) play a crucial role in migraine pathophysiology. In recent years, anti-CGRP(R) monoclonal antibodies (mAbs) have emerged as the first targeted and highly effective therapy for migraine. This study aimed to assess any changes in plasma CGRP levels following prophylactic treatment with anti-CGRP(R) mAbs and to compare CGRP dynamics between anti-receptor (erenumab) and anti-ligand (galcanezumab, fremanezumab) therapies. Secondary objectives were: (i) to evaluate changes in VIP and PACAP plasma levels following treatment with anti-CGRP(R) mAbs and (ii) to investigate whether baseline or post-treatment plasma levels of CGRP, VIP and PACAP were associated with clinical response to anti-CGRP(R) monoclonal antibody therapy. Methods: Between February 2022 and February 2023, we enrolled 56 migraine patients who initiated prophylaxis with either erenumab (26 patients), galcanezumab (16 patients) or fremanezumab (14 patients). Responders were defined as those achieving a ≥50% reduction in monthly migraine days after six months. Blood samples were collected at baseline and at each follow-up visit (baseline, T0; three months, T1; six months, T2; 12 months, T3). Plasma levels of CGRP, VIP and PACAP were measured using a validated radioimmunoassay and commercially available enzyme-linked immunosorbent assay kits. Results: Overall, 80.3% (45 out of 56) of patients responded to anti-CGRP(R) mAbs. No correlation was found between baseline CGRP, VIP and PACAP plasma levels and clinical response to anti-CGRP(R) mAbs therapy. Regarding CGRP trend, significant differences were found between patients treated with the anti-receptor monoclonal antibody (erenumab) and those receiving anti-ligand therapies. In patients treated with erenumab, CGRP levels did not show a significant change over the treatment period (T1–T3), whereas, in the galcanezumab group, CGRP levels significantly decreased as early as T1 ( p < 0.01). CGRP longitudinal assessment of the fremanezumab group were excluded due to assay interference with the drug. VIP and PACAP plasma levels remained stable over time for all treatments, with no significant differences between responders and non-responders. Conclusions: Galcanezumab reduced CGRP plasmatic levels already after three months, whereas erenumab did not affect significantly CGRP plasmatic levels. VIP and PACAP levels were not influenced by the therapy.