Current Alzheimer Research - Volume 18, Issue 8, 2021

Background: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated Type 2 Diabetes Mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer´s Disease (AD)-like amyloid-β (Aβ) pathology, reducing the Aβ plaque load, microgliosis and astrocytosis in the hippocampus and cortex. Objective: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aβ plaques contribute to cognitive deficits in AD. Methods: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice. Results: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aβ plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker Glial Fibrillary Acidic Protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aβ plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice. Conclusion: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.

Background: Alzheimer's disease (AD) is a neurological disorder characterized by loss of memory and cognitive functions caused by oxidative stress, neuroinflammation, change in neurotransmitter levels, and excessive deposition of Aβ(1-42) plaques. Fucoxanthin is a carotenoid with potential antioxidant, anti-inflammatory, and neuroprotective actions. Objective: In the present study, fucoxanthin was employed as a protective strategy in Intracerebroventricular Streptozotocin (ICV-STZ) induced experimental model of cognitive impairment. Methods: STZ was injected twice ICV (3 mg/kg) on alternate days 1 and 3, and Wistar rats were evaluated for the memory analysis using Morris water maze and elevated plus-maze. Fucoxanthin at low 50 mg/kg, p.o. and high dose 100 mg/kg, p.o. was administered for 14 days. All animals were sacrificed on day 29, and brain hippocampus tissue after isolation was used for biochemical (MDA, nitrite, GSH, SOD and Catalase), neuroinflammatory (TNF-α, IL-1β, and IL-6), neurotransmitters (ACh, GABA Glutamate), Aβ(1-42) and Tau protein measurements. Results: STZ-infused rats showed significant impairment in learning and memory, increased oxidative stress (MDA, nitrite), reduced antioxidant defense (GSH, SOD and Catalase), promoted cytokine release, and change in neurotransmitters level. However, fucoxanthin improved cognitive functions, restored antioxidant levels, reduced inflammatory markers dose-dependently, and restored neurotransmitters concentration. Conclusion: The finding of the current study suggests that fucoxanthin could be the promising compound for improving cognitive functions through antioxidant, anti-inflammatory, and neuroprotective mechanisms, and inhibition of acetylcholinesterase (AChE) enzyme activities, Aβ(1-42) accumulation, and tau protein.

Background: The independent effect of physical work on the risk of cognitive impairment in older Chinese older adults living in rural areas remains to be elucidated. Objective: We aimed to determine whether physical work and physical exercise can reduce the risk of cognitive impairment. Methods: We collected data from 7,000 permanent residents without cognitive impairment (age ≥60 years) over a follow-up period of 2 years. We used the Chinese version of the Mini-Mental State Examination (MMSE) to assess cognitive function. We performed multivariate Cox regression analyses to calculate adjusted Hazard Ratios (HRs) and 95% Confidence Intervals (%95 CIs) as measures of the association between physical work/exercise and cognitive impairment while controlling for potential confounders. Results: Over a median follow-up period of 1.93 years, 1,224 (17.5%) of 7,000 participants developed cognitive impairment, with a total incidence of 97.69 per 1,000 person-years. After adjustment for potential confounders, participating in physical work (HR: 0.51; 95% CI: 0.43-0.60) or physical exercise (HR: 0.53; 95% CI: 0.44-0.65) was associated with a reduced risk of cognitive impairment. Stratified analyses suggested additive and multiplicative interactions between physical work and exercise. Agricultural work (HR: 0.46; 95% CI: 0.38-0.55), walking/tai chi (HR: 0.54; 95% CI: 0.44-0.67), and brisk walking/yangko (HR: 0.57; 95% CI: 0.33-0.97) exerted significant protective effects against cognitive impairment. Conclusion: Both physical work and exercise can reduce the risk of cognitive impairment in older adults. Reasonable types and appropriate intensities of physical activity are recommended to prevent or delay the progression of cognitive impairment.

Purpose: The aim of this study was to investigate the differences in early (EOAD) and late (LOAD) onset of Alzheimer´s disease, as well as glucose uptake, regional cerebral blood flow (R1), amyloid depositions, and functional brain connectivity between normal young (YC) and Old Controls (OC). Methodology: The study included 22 YC (37 ± 5 y), 22 OC (73 ± 5.9 y), 18 patients with EOAD (63 ± 9.5 y), and 18 with LOAD (70.6 ± 7.1 y). Patients underwent FDG and PIB PET/CT. R1 images were obtained from the compartmental analysis of the dynamic PIB acquisitions. Images were analyzed by a voxel-wise and a VOI-based approach. Functional connectivity was studied from the R1 and glucose uptake images. Results: OC had a significant reduction of R1 and glucose uptake compared to YC, predominantly at the dorsolateral and mesial frontal cortex. EOAD and LOAD vs. OC showed a decreased R1 and glucose uptake at the posterior parietal cortex, precuneus, and posterior cingulum. EOAD vs. LOAD showed a reduction in glucose uptake and R1 at the occipital and parietal cortex and an increased at the mesial frontal and temporal cortex. There was a mild increase in an amyloid deposition at the frontal cortex in LOAD vs. EOAD. YC presented higher connectivity than OC in R1 but lower connectivity considering glucose uptake. Moreover, EOAD and LOAD showed a decreased connectivity compared to controls that were more pronounced in glucose uptake than R1. Conclusion: Our results demonstrated differences in amyloid deposition and functional imaging between groups and a differential pattern of functional connectivity in R1 and glucose uptake in each clinical condition. These findings provide new insights into the pathophysiological processes of AD and may have an impact on patient diagnostic evaluation.

Background: Lipoprotein Lipase (LPL) is the rate-limiting enzyme catalyzing the hydrolysis of triglycerides and contributes to the amyloid-β formation, which shows promise as a pathological factor of cognitive decline in Type 2 Diabetes Mellitus (T2DM). This study aimed to investigate the pathogenetic roles of LPL and rs328 polymorphism in Mild Cognitive Impairment (MCI) in patients with T2DM. Methods: Chinese patients with T2DM were recruited and divided into two groups based on the Montreal Cognitive Assessment score. Demographic data were collected, LPL was measured and neuropsychological test results were examined. Results: Seventy-nine patients with diabetes and MCI had significantly decreased plasma LPL levels (p = 0.007) when compared with health-cognition controls (n = 91). Correlation analysis revealed that LPL was positively correlated with clock drawing test (r = 0.158, p = 0.043) and logical memory test (r = 0.162, p = 0.037), while lipoprotein a (r = -0.214, p = 0.006) was inversely associated with LPL. Logistic regression analysis further demonstrated that LPL concentration was an independent factor for diabetic MCI (p = 0.036). No significant differences were observed in the distributions of rs328 variants between patients with MCI and the controls. Moreover, no remarkable association was found among plasma LPL levels, cognitive performances, and lipid levels between the genotypic subgroups. The trail making test A was increased in the GC group when compared with the CC genotype in the control group. Conclusion: Decreased plasma level of LPL could probably predict early cognitive deficits, especially verbal disfluency.