Superiority of the Triple-Acting 5-HT6R/5-HT3R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT6R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats.

The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT6R antagonism and interaction with 5-HT3R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT6R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-ß peptide (oAß) in the T-maze test in rats. PZ-1922, but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAß. These data support the potential of a multitarget approach involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD.

Intranasal Administration of Nanovectorized Docosahexaenoic Acid (DHA) Improves Cognitive Function in Two Complementary Mouse Models of Alzheimer's Disease.

Polyunsaturated fatty acids (PUFAs) are a class of fatty acids that are closely associated with the development and function of the brain. The most abundant PUFA is docosahexaenoic acid (DHA, 22:6 n-3). In humans, low plasmatic concentrations of DHA have been associated with impaired cognitive function, low hippocampal volumes, and increased amyloid deposition in the brain. Several studies have reported reduced brain DHA concentrations in Alzheimer's disease (AD) patients' brains. Although a number of epidemiological studies suggest that dietary DHA consumption may protect the elderly from developing cognitive impairment or dementia including AD, several review articles report an inconclusive association between omega-3 PUFAs intake and cognitive decline. The source of these inconsistencies might be because DHA is highly oxidizable and its accessibility to the brain is limited by the blood-brain barrier. Thus, there is a pressing need for new strategies to improve DHA brain supply. In the present study, we show for the first time that the intranasal administration of nanovectorized DHA reduces Tau phosphorylation and restores cognitive functions in two complementary murine models of AD. These results pave the way for the development of a new approach to target the brain with DHA for the prevention or treatment of this devastating disease.

Seizure activity triggers tau hyperphosphorylation and amyloidogenic pathways.

OBJECTIVE: Although epilepsies and neurodegenerative disorders show pathophysiological similarities, their direct functional associations are unclear. Here, we tested the hypothesis that experimental seizures can induce tau hyperphosphorylation and amyloidogenic modifications over time, with intersections with neuroinflammation. METHODS: We used a model of mesial temporal lobe epilepsy (MTLE) where unilateral intrahippocampal injection of kainic acid (KA) in C57BL/6 mice elicits epileptogenesis and spontaneous focal seizures. We used a model of generalized status epilepticus (SE) obtained by intraperitoneal KA injection in C57BL/6 mice. We performed analyses and cross-comparisons according to a schedule of 72 h, 1 week, and 8 weeks after KA injection. RESULTS: In experimental MTLE, we show AT100, PHF1, and CP13 tau hyperphosphorylation during epileptogenesis (72 h-1 week) and long-term (8 weeks) during spontaneous seizures in the ipsilateral hippocampi, the epileptogenic zone. These pathological modifications extended to the contralateral hippocampus, a seizure propagating zone with no histological lesion or sclerosis. Two kinases, Cdk5 and GSK3ß, implicated in the pathological phosphorylation of tau, were activated. In this MTLE model, the induction of the amyloidogenic pathway (APP, C99, BACE1) was prominent and long-lasting in the epileptogenic zone. These Alzheimer's disease (AD)-relevant markers, established during seizure progression and recurrence, reciprocated an enduring glial (GFAP, Iba1) inflammation and the inadequate activation of the endogenous, anti-inflammatory, glucocorticoid receptor system. By contrast, a generalized SE episode provoked a predominantly transient induction of tau hyperphosphorylation and amyloidogenic markers in the hippocampus, along with resolving inflammation. Finally, we identified overlapping profiles of long-term hippocampal tau hyperphosphorylation by comparing MTLE to J20 mice, the latter a model relevant to AD. SIGNIFICANCE: MTLE and a generalized SE prompt persistent and varying tau hyperphosphorylation or amyloidogenic modifications in the hippocampus. In MTLE, an AD-relevant molecular trajectory intertwines with neuroinflammation, spatiotemporally involving epileptogenic and nonlesional seizure propagating zones.