JoAnne McLaurin

Interaction between therapeutic interventions for Alzheimer's disease and physiological Aβ clearance mechanisms.

Most therapeutic agents are designed to target a molecule or pathway without consideration of the mechanisms involved in the physiological turnover or removal of that target. In light of this and in particular for Alzheimer’s disease, a number of therapeutic interventions are presently being developed/investigated which target the amyloid-β peptide (Aβ). However, the literature has not adequately considered which Aβ physiological clearance pathways are necessary and sufficient for the effective action of these therapeutics. In this review, we evaluate the therapeutic strategies targeting Aβ presently in clinical development, discuss the possible interaction of these treatments with pathways that under normal physiological conditions are responsible for the turnover of Aβ and highlight possible caveats. We consider immunization strategies primarily reliant on a peripheral sink mechanism of action, small molecules that are reliant on entry into the CNS and thus degradation pathways within the brain, as well as lifestyle interventions that affect vascular, parenchymal and peripheral degradation pathways. We propose that effective development of Alzheimer’s disease therapeutic strategies targeting Aβ peptide will require consideration of the age- and disease-specific changes to endogenous Aβ clearance mechanisms in order to elicit maximal efficacy.

Impaired Cholinergic Excitation of Prefrontal Attention Circuitry in the TgCRND8 Model of Alzheimer's Disease

Attention deficits in Alzheimers disease can exacerbate its other cognitive symptoms, yet relevant disruptions of key prefrontal circuitry are not well understood. Here, in the TgCRND8 mouse model of this neurological disorder, we demonstrate and characterize a disruption of cholinergic excitation in the major corticothalamic layer of the prefrontal cortex, in which modulation by acetylcholine is essential for optimal attentional function. Using electrophysiology with concurrent multiphoton imaging, we show that layer 6 pyramidal cells are unable to sustain cholinergic excitation to the same extent as their nontransgenic littermate controls, as a result of the excessive activation of calcium-activated hyperpolarizing conductances. We report that cholinergic excitation can be improved in TgCRND8 cortex by pharmacological blockade of SK channels, suggesting a novel target for the treatment of cognitive dysfunction in Alzheimers disease. SIGNIFICANCE STATEMENT Alzheimers disease is accompanied by attention deficits that exacerbate its other cognitive symptoms. In brain slices of a mouse model of this neurological disorder, we demonstrate, characterize, and rescue impaired cholinergic excitation of neurons essential for optimal attentional performance. In particular, we show that the excessive activation of a calcium-activated potassium conductance disrupts the acetylcholine excitation of prefrontal layer 6 pyramidal neurons and that its blockade normalizes responses. These findings point to a novel potential target for the treatment of cognitive dysfunction in Alzheimers disease.

Early stage attenuation of phase amplitude coupling in the hippocampus and medial prefrontal cortex in a transgenic rat model of AD

Alzheimers disease (AD) is pathologically characterized by amyloid‐β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aβ‐dependent neuronal dysfunction including modulation of gamma‐aminobutyric acid‐ergic signaling. The present work focuses on the early stage of disease progression and uses TgF344‐AD rats that recapitulate a broad repertoire of AD‐like pathologies to investigate the neuronal network functioning using simultaneous intracranial recordings from the hippocampus (HPC) and the medial prefrontal cortex (mPFC), followed by pathological analyses of gamma‐aminobutyric acid (GABAA) receptor subunits α1, α5, and δ, and glutamic acid decarboxylases (GAD65 and GAD67). Concomitant to amyloid deposition and tau hyperphosphorylation, low‐gamma band power was strongly attenuated in the HPC and mPFC of TgF344‐AD rats in comparison to those in non‐transgenic littermates. In addition, the phase‐amplitude coupling of the neuronal networks in both areas was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude in TgF344‐AD animals. Finally, the gamma coherence between HPC and mPFC was attenuated as well. These results demonstrate significant neuronal network dysfunction at an early stage of AD‐like pathology. This network dysfunction precedes the onset of cognitive deficits and is likely driven by Aβ and tau pathologies.

Rho-associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease

The causes of late‐onset Alzheimers disease are unclear and likely multifactorial. Rho‐associated protein kinases (ROCKs) are ubiquitously expressed signaling messengers that mediate a wide array of cellular processes. Interestingly, they play an important role in several vascular and brain pathologies implicated in Alzheimers etiology, including hypertension, hypercholesterolemia, blood–brain barrier disruption, oxidative stress, deposition of vascular and parenchymal amyloid‐beta peptides, tau hyperphosphorylation, and cognitive decline. The current review summarizes the functions of ROCKs with respect to the various risk factors and pathologies on both sides of the blood–brain barrier and present support for targeting ROCK signaling as a multifactorial and multi‐effect approach for the prevention and amelioration of late‐onset Alzheimers disease.

FUNCTIONAL AND PATHOLOGICAL CHARACTERIZATION OF THE BRAIN MICROVASCULATURE IN A RAT MODEL OF ALZHEIMER'S DISEASE

emerged from groundbreaking discoveries in the past few years on content of extracellular vesicles(EVs). EVs have been demonstrated to facilitate horizontal transfer of miRNAs and proteins between cells without direct cell-to-cell contact. Based on this background, the objective of this study was to characterize EMVs from MSC and evaluate the neuroprotective actions of EVs against the deleterious effects caused by exposure of hippocampal neurons to ADDLs. Methods:EVs characterization was performed by Flow cytometry, ElectronMicroscopy and Nanoparticle Tracking Analysis.Neuroprotection against OS was verified by general oxidative stress indicator and EVs enzyme content by Oroboros oxygraph. Moreover, we evaluate MSC’s miRNA expression profile and released through EVs in Next Generation Sequencing and EV’s miRNA internalization in neurons. Results: Our results indicate that EVs have markers of MSC membrane, and its peak release between 3 and 5 hours after cell stress. The internalization rate of EVs in neurons is increased when the neurons are subjected to ADDLs and it is is followed by miRNAs transfer into the cell. The presence of EVs in culture protected neurons against OS generated by exposure to ADDLs to control levels. Our hypothesis that this protection is based on the presence of catalase in content of EVs, proven by Oroboros oxygraph. Conclusions:Obtained results show the potential of EVs in treatment against damage by OS in AD.

FOCUSED ULTRASOUND-MEDIATED DELIVERY OF NATURAL ANTIBODIES TO THE BRAIN FACILITATES NEURONAL PLASTICITY IN AN AMYLOIDOSIS MOUSE MODEL

any significant effects. There were no significant effects of gender or the interaction of ethnicity and gender on any analyte. Conclusions:Ab42 is more associated with disease states, including AD, and is the more amyloidogenic form. S100B is expressed by astrocytes and increased levels in CSF have been described in mild-moderate AD. Serum S100B levels are thought to be a peripheral biomarker of blood-brain-barrier permeability or CNS injury. Overall, these preliminary results provide support for increased neurodegeneration in AAwith AD. The mechanistic implications of these levels will require further research. Our future studies include measurement of inflammatory proteins in this brain region as well as investigation of potential mechanisms, including potential ethnicity-related SNP differences in specific genes.

Venular degeneration in the pathogenesis of Alzheimer's disease

was associated with AD (p1⁄49E-4). We then examined overlapping SNPs in adults with DS, and found rs2378991 to be associated with AD as well as age at onset (p1⁄40.04). Lastly, hippocampal neuron survival assay showed that knocking down CUGBP2 protects neurons from Ab toxicity. Conclusions: Our multi-stage study showed that genetic factors in CUGBP2 are likely to be involved in AD, and may work through the amyloid pathway.