Neurovascular mechanisms of cognitive aging: Sex-related differences in the average progression of arteriosclerosis, white matter atrophy, and cognitive decline.

Arterial stiffness (arteriosclerosis) has been linked to heightened risks for cognitive decline, and ultimately for Alzheimer's disease and other forms of dementia. Importantly, neurovascular outcomes generally vary according to one's biological sex. Here, capitalizing on a large sample of participants with neuroimaging and behavioral data (N = 203, age range = 18-87 years), we aimed to provide support for a hierarchical model of neurocognitive aging, which links age-related declines in cerebrovascular health to the rate of cognitive decline via a series of intervening variables, such as white matter integrity.

Effects of Aging, Fitness, and Cerebrovascular Status on White Matter Microstructural Health.

White matter (WM) microstructural health declines with increasing age, with evidence suggesting that improved cardiorespiratory fitness (CRF) may mitigate this decline. Specifically, higher fit older adults tend to show preserved WM microstructural integrity compared to their lower fit counterparts. However, the extent to which fitness and aging impact WM integrity across the adult lifespan is still an open question, as is the extent to which cerebrovascular health mediates these relationships.

Domoic Acid as a Lead for the Discovery of the First Selective Ligand for Kainate Receptor Subtype 5 (GluK5).

Twenty-one simplified analogues of the natural product domoic acid were designed, synthesized, and then characterized at homomeric kainic acid (KA) receptors (GluK1-3,5). displays a high affinity for homomeric GluK5 receptors (IC = 432 nM) with a >40-fold selectivity over homomeric GluK1-3 subtypes and ≫100-fold selectivity over native AMPA and -methyl d-aspartate receptors. Functional studies of on heteromeric GluK2/5 receptors show no agonist or antagonist functional response at 10 μM, while a concentration of 100 μM at neuronal slices (rat) shows low agonist activity.

Crystal structure of the GluK1 ligand-binding domain with kainate and the full-spanning positive allosteric modulator BPAM538.

Kainate receptors play an important role in the central nervous system by mediating postsynaptic excitatory neurotransmission and modulating the release of the inhibitory neurotransmitter GABA through a presynaptic mechanism. To date, only three structures of the ligand-binding domain (LBD) of the kainate receptor subunit GluK1 in complex with positive allosteric modulators have been determined by X-ray crystallography, all belonging to class II modulators. Here, we report a high-resolution structure of GluK1-LBD in complex with kainate and BPAM538, which belongs to the full-spanning class III.

Osteopontin: A novel marker of pre-symptomatic sporadic Alzheimer's disease.

Introduction: We investigate the role of osteopontin (OPN) in participants with Pre-symptomatic Alzheimer's disease (AD), mild cognitive impairment (MCI), and in AD brains.

Methods: Cerebrospinal fluid (CSF) OPN, AD, and synaptic biomarker levels were measured in 109 cognitively unimpaired (CU), parental-history positive Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) participants, and in 167 CU and 399 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. OPN levels were examined as a function of amyloid beta (Aβ) and tau positivity.