Current Alzheimer Research - Volume 20, Issue 1, 2023

Memory is empirically described as a brain function that connects the past to the present. This reductionist approach has focused on memory function within neurons and synapses, leading to an understanding that memory loss in dementia is caused by irreversible neuronal damage. However, recent palliative case reports and the Human Connectome Project have challenged the "irreversible" paradigm by indicating that some demented patients are able to retrieve supposed ‘lost’ memories and cognitive functions near death. The serotonin-centric hypothesis and the lifelong oligodendrocyte differentiation capacity may explain terminal awakening symptoms in these patients. Furthermore, an increased rate of serotonin-secreting and oligodendrocyte precursor cell-triggering gut bacteria near death temporally correlates with lucid improvements in demented patients. These findings may shift the context of terminal memory retrieval from a purely neuronal to a systemic idea that bridges terminal lucidity and gut microbiota. In this review, we take the systemic approach further and point out a temporal correlation between the gut microbiome and terminal lucid episodes in Alzheimer’s patients.

Objective: To explore changes in the alpha rhythm wavelength of background electroencephalography in Alzheimer’s disease patients with different degrees of dementia in a resting state; examine their correlation with the degree of cognitive impairment; determine whether the alpha rhythm wavelength can distinguish mild Alzheimer’s disease patients, moderately severe Alzheimer’s disease patients, and healthy controls at the individual level; and identify a cut-off value to differentiate Alzheimer’s disease patients from healthy controls. Methods: Quantitative electroencephalography signals of 42 patients with mild Alzheimer’s disease, 42 patients with moderately severe Alzheimer’s disease, and 40 healthy controls during rest state with eyes closed were analyzed using wavelet transform. Electroencephalography signals were decomposed into different scales, and their segments were superimposed according to the same length (wavelength and amplitude) and phase alignment. Phase averaging was performed to obtain average phase waveforms of the desired scales of each lead. The alpha-band wavelengths corresponding to the ninth scale of the background rhythm of different leads were compared between groups. Results: The average wavelength of the alpha rhythm phase of the whole-brain electroencephalography signals in Alzheimer’s disease patients was prolonged and positively correlated with the severity of cognitive dysfunction (P < 0.01). The ninth-scale phase average wavelength of each lead had high diagnostic efficacy for Alzheimer’s disease, and the diagnostic efficacy of lead P3 (area under the receiver operating characteristic curve = 0.873) was the highest. Conclusion: The average wavelength of the electroencephalography alpha rhythm phase may be used as a quantitative feature for the diagnosis of Alzheimer’s disease, and the slowing of the alpha rhythm may be an important neuro-electrophysiological index for disease evaluation.

Objective: The objective of this study is to investigate the neuroprotective effects of β- sitosterol using the AlCl3 model of Alzheimer's Disease. Methods: AlCl3 model was used to study cognition decline and behavioral impairments in C57BL/6 mice. Animals were randomly assigned into 4 groups with the following treatments: Group 1 received normal saline for 21 days, Group 2 received AlCl3 (10 mg/kg) for 14 days; Group 3 received AlCl3(10 mg/kg) for 14 days + β-sitosterol (25mg/kg) for 21 days; while Group 4 was administered β-sitosterol (25mg/kg) for 21 days. On day 22, we performed the behavioral studies using a Y maze, passive avoidance test, and novel object recognition test for all groups. Then the mice were sacrificed. The corticohippocampal region of the brain was isolated for acetylcholinesterase (AChE), acetylcholine (ACh), and GSH estimation. We conducted histopathological studies using Congo red staining to measure β -amyloid deposition in the cortex and hippocampal region for all animal groups. Results: AlCl3 successfully induced cognitive decline in mice following a 14-day induction period, as shown by significantly decreased (p < 0.001) in step-through latency, % alterations, and preference index values. These animals also exhibited a substantial decrease in ACh (p <0.001) and GSH (p < 0.001) and a rise in AChE (p < 0.001) compared to the control group. Mice administered with AlCl3 and β-sitosterol showed significantly higher step-through latency time, % alteration time, and % preference index (p < 0.001) and higher levels of ACh, GSH, and lower levels of AChE in comparison to the AlCl3 model. AlCl3-administered animals also showed higher β-amyloid deposition, which got significantly reduced in the β-sitosterol treated group. Conclusion: AlCl3 was effectively employed to induce a cognitive deficit in mice, resulting in neurochemical changes and cognitive decline. β -sitosterol treatment mitigated AlCl3-mediated cognitive impairment.

Background: Microglial overactivation promotes the production of various second messengers and inflammatory markers in brain tissue, resulting in neuroinflammation and neurodegeneration, which may lead to cognitive decline. The cyclic nucleotides are one of the important second messengers involved in the regulation of neurogenesis, synaptic plasticity, and cognition. The levels of these cyclic nucleotides are maintained by phosphodiesterase enzyme isoforms, particularly PDE4B, in the brain. An imbalance between PDE4B levels and cyclic nucleotides may lead to aggravating neuroinflammation. Methods: Lipopolysaccharides (LPS) were administered intraperitoneally on alternate days for 7 days at a dose of 500 μg/kg in mice, which triggered systemic inflammation. This may lead to the activation of glial cells and may activate oxidative stress and neuroinflammatory markers in brain tissue. Furthermore, oral administration of roflumilast (0.1, 0.2, and 0.4 mg/kg) in this model ameliorated oxidative stress markers, neuroinflammation and improved neurobehavioral parameters in these animals. Results: The detrimental effect of LPS increased oxidative stress, AChE enzyme levels, and decreased catalase levels in brain tissues, along with memory impairment in animals. Moreover, it also enhanced the activity and expression of the PDE4B enzyme, resulting in a decline in cyclic nucleotide levels. Furthermore, treatment with roflumilast improved the cognitive decline, decreased AChE enzyme level, and increased the catalase enzyme level. Roflumilast also reduced the PDE4B expression in a dose-dependent manner, which LPS up-regulated. Conclusion: Roflumilast has shown an anti-neuroinflammatory effect and reversed the cognitive decline in LPS-induced mice model.

Background: Traditional Chinese medicine (TCM) indicates that Alzheimer's disease (AD) is considered the consequence produced by Kidney Yang Deficiency Syndrome (KDS-Yang), which has similar clinical characteristics to glucocorticoid withdrawal syndrome. Ginsenoside Re (G-Re) has been found to ameliorate the symptoms and pathological impairments of AD. However, it's not clear whether G-Re could protect memory and synapse lesions against kidney deficiency dementia. Methods: Subcutaneous injection of hydrocortisone for 14 days was used to produce KDS-Yang. On the 15th day, Aβ25-35 peptide was injected into the intracerebroventricular (icv) of KDS-Yang rats. Spine density was analyzed by Golgi staining and the ultrastructural morphology of the synapse was detected using Transmission Electron Microscopy (TEM). Western blot was used to examine the expression of pS396, pS404, Tau-5, tGSK-3β, pS9GSK-3β, Syt, Syn I, GluA1, GluN2B, PSD93, PSD95, β2-AR and pS346-b2-AR. Results: Hyperphosphorylation of tau in Aβ25-35-injected rats with KDS-Yang was stronger than in Aβ25-35-injected rats at the sites of Ser396 and Ser404. G-Re improved spatial memory damage detected by Morris water-maze (MWM), enhanced spines density, the thickness of postsynaptic density (PSD) and increased the expression of Syt, Syn I, GluA1, GluN2B, PSD93 and PSD95. Moreover, GRe decreased the hyperphosphorylation of β2-AR at serine 346 in Aβ25-35-injected rats with KDS-Yang. Conclusion: KDS-Yang might exacerbate AD pathological lesions. Importantly, G-Re is a potential ingredient for protecting against memory and synapse deficits in kidney deficiency dementia.