Current Alzheimer Research - Volume 21, Issue 10, 2024

Alzheimer's Disease (AD) is a long-term brain disorder that worsens over time. A cholinesterase inhibitor called Donepezil HCl (DNZ) is used to treat and control AD. Due to its failure to reach the appropriate concentration in the brain cells, its efficacy upon oral administration is limited, and thus investigation of alternative administration route is necessary.

The objective of this study was to develop donepezil HCl-loaded Nanostructured Lipid Carriers (NLCs) that can bypass the blood-brain barrier and thus be directly delivered to the brain through the nasal route. This method improves availability at the site of action, reduces the negative effects of oral medication, and ensures an expedited commencement of action.

High-pressure homogenization and ultrasonication were used to formulate NLCs. Glyceryl Monostearate (GMS) as a solid lipid, Tween 80 as a surfactant, and Poloxamer 407 as a co-surfactant were used. In this study, argan oil was employed as a liquid lipid as well as a penetration enhancer.

The chosen NLCs displayed a particle size of 137.34 ± 0.79 nm, a PDI of 0.365 ± 0.03, and a zeta potential of -10.4 mV. The selected formulation showed an entrapment efficiency of 84.05 ± 1.30% and a drug content of 77.02 ± 0.23%. The concentration of the drug in the brain after intravenous and intranasal administration of DNZ NLCs at 1 h was found to be 0.490 ± 0.007 and 4.287 ± 0.115, respectively. Thus, the concentration of DNZ achieved in the brain after intranasal administration of DNZ NLCs was approximately 9 times more than the concentration when administered by intravenous route.

The DNZ-loaded NLCs, when administered via nasal route, showed markedly improved drug availability in the brain, suggesting an efficient drug delivery strategy to treat Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological disorder for which no effective cure currently exists. Research has identified β-Secretase (BACE1) as a promising therapeutic target for the management of AD. BACE1 is involved in the rate-limiting step and produces toxic amyloid-beta (Aβ) peptides that lead to deposits in the form of amyloid plaques extracellularly, resulting in AD.

In this connection, 60 small peptides were evaluated for their in-silico studies to predict the bonding orientation with BACE1. Next, 5 peptides (12, 20, 21, 51, and 52) were selected based on high scoring of Vander Waal interactions with the catalytic site of the enzyme.

The identified hit peptides were synthesized using Solid-Phase Peptide Synthesis (SPPS), and Electrospray Ionization Mass Spectrometry (ESI-MS) elucidated their structures and 1 1 H-NMR spectroscopy. According to their In-vitro BACE1 inhibitory study, peptides 21 having high Vander Waal forces showed significant BACE1 inhibition with IC50 = 4.64 ± 0.1µM). Moreover, the kinetic study revealed that peptide 21 is a mixed-type inhibitor and can interact at the active site and the allosteric site of BACE1.

According to the cytotoxicity study, peptide 21 was found to be noncytotoxic at 4.64 µM, 10 µM and 20 µM. The forthcoming target of this study is to evaluate further the effect of peptide 21 in an in-vivo mice model.

Muscarinic 1 acetylcholine receptor (M1AChR) is a member of the G-protein-coupled receptor superfamily, with the dysfunction being linked to the onset of Alzheimer's Disease (AD).

Retromer complex with Vacuolar Protein Sorting-35 (VPS35) as the core plays an important role in the transport of biological proteins and has been confirmed to be closely related to the pathogenesis of AD. This study was designed to determine whether VPS35 could affect the trafficking mechanism of M1AChRs.

The interaction between VPS35 and M1AChR was studied by co-immunoprecipitation method, and the recycling of M1AChR influence by VPS35 was analyzed using biotinylation technology.

It was found that VPS35 affected the localization of M1AChR on the cell membrane by regulating intracellular M1AChR transport, thus controlling the M1AChR-mediated cholinergic signaling pathway.

The findings presented here provide a potential pathogenesis and pathway for the treatment of AD.

For over a decade, AMPA receptor allosteric potentiators (AMPAkines) have shown significant effectiveness in multiple preclinical studies related to neurodegenerative and psychiatric disorders underpinned by deficient excitatory synaptic activity. Despite promising preclinical evidence, the clinical translation of AMPAkines has been slow due to the propensity of some of these compounds to produce seizures at or around therapeutic doses.

The preclinical activity of the AMPAkine CX1837 is disclosed in the current work.

CX1837 enhanced synaptic transmission in hippocampal slices in vitro and dose-dependently enhanced long-term potentiation, which is believed to control memory consolidation. CX1837 boosted performance in cognition tests, such as the novel object recognition test and the win-shift radial arm maze. CX1837 also increased attentional functioning in the 5-choice serial re-action time task in rats. CX1837 produced positive preclinical effects at 0.01-1.0 mg/kg dose and elicited epileptic effects at 10 mg/kg dose.

CX1837 has one of the largest safety margins to date in preclinical studies. Low doses of CX1837, which produce acute increases in cognition, may potentially increase neurotrophins when given chronically. This could slow the progression of Alzheimer’s disease and reverse deficits secondary to ischemic stroke.

Together, our findings highlight CX1837 as a potential candidate for clinical development in order to treat multiple neurodegenerative and psychiatric disorders.

The rapid growth of mobile phone use and internet access among older adults can provide valuable opportunities for clinicians and researchers to incorporate these technologies into the memory rehabilitation of patients with Alzheimer’s disease (AD). Building on this opportunity, previous research has used smartphone calendar applications to cue prospective memory in patients with AD. However, in these studies, the calendar has been programmed to send cues only about the time of prospective events.

We investigated the benefits of the smartphone calendar applications sending notifications about both the time and location of the prospective events. We recruited two groups. In the first group (time-and-location-cued group), we configured smartphone-based calendars to send notifications about the time and location of prospective events, while in the second group (time-cued group), we configured smartphone-based calendars to send notifications only about the time of prospective events. In both groups, we invited patients to attend three prospective events per week during a three-week period.

The results demonstrated fewer omissions in the time- and location-cued group than in the time-cued group.

Providing patients with AD with several contextual cues through smartphone-based calendars may result in better prospective performance than providing them with only one contextual cue.