Familial Alzheimer\'s disease (FAD) presenilin 1 E280A (PSEN1 E280A) is a severe neurological condition due to the loss of cholinergic neurons (ChNs), accumulation of amyloid beta (Aβ), and abnormal phosphorylation of the TAU protein. Up to date, there are no effective therapies available. The need for innovative treatments for this illness is critical. We found that minocycline (MC, 5 μM) was innocuous toward wild-type (WT) PSEN1 ChLNs but significantly (i) reduces the accumulation of intracellular Aβ by -69%, (ii) blocks both abnormal phosphorylation of the protein TAU at residue Ser202/Thr205 by -33% and (iii) phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by -25%, (iv) diminishes oxidized DJ-1 at Cys106-SO3 by -29%, (v) downregulates the expression of transcription factor TP53, (vi) BH-3-only protein PUMA, and (vii) cleaved caspase 3 (CC3) by -33, -86, and -78%, respectively, compared with untreated PSEN1 E280A ChLNs. Additionally, MC increases the response to ACh-induced Ca2+ influx by +92% in mutant ChLNs. Oxygen radical absorbance capacity (ORAC) and ferric ion-reducing antioxidant power (FRAP) analysis showed that MC might operate more efficiently as a hydrogen atom transfer agent than a single electron transfer agent. In silico molecular docking analysis predicts that MC binds with high affinity to Aβ (Vina Score -6.6 kcal/mol), TAU (VS -6.5 kcal/mol), and caspase 3 (VS -7.1 kcal/mol). Taken together, our findings suggest that MC demonstrates antioxidant, anti-amyloid, and anti-apoptosis activity and promotes physiological ACh-induced Ca2+ influx in PSEN1 E280A ChLNs. The MC has therapeutic potential for treating early-onset FAD.

The amyloid beta (Aβ) 42/40 ratio has been widely studied as a biomarker in Alzheimer\'s disease (AD); however, other Aβ peptides could also represent relevant biomarkers. We measured levels of Aβ38/40/42 in plasma samples from cognitively-unimpaired older adults and determined the relationships between Aβ levels and amyloid positron-emission-tomography (PET) and performance on a learning and memory task. We found that all Aβ peptides individually and the Aβ42/40 ratio, but not the Aβ42/38 ratio, were significantly correlated with brain amyloid (Aβ-PET). Multiple linear modeling, adjusting for age, sex, education, APOE4 and Aβ-PET showed significant associations between the Aβ42/38 ratio and memory. Further, associations between the Aβ42/38 ratio and learning scores were stronger in males and in Aβ-PET-negative individuals. In contrast, no significant associations were detected between the Aβ42/40 ratio and any learning measure. These studies implicate the Aβ42/38 ratio as a biomarker to assess early memory deficits and underscore the utility of the Aβ38 fragment as an important biomarker in the AD field.

Alzheimer\'s disease (AD) stands as the predominant contributor to dementia cases. The ongoing developments in our understanding of its pathogenesis have sparked the interest of researchers, driving them to explore innovative treatment approaches. Existing therapies incorporating cholinesterase inhibitors and/or NMDA antagonists have shown limited improvement in alleviating symptoms. This, in turn, highlights the urgency for the pursuit of more effective therapeutic options. Given the annual rise in the number of individuals affected by dementia, it is imperative to allocate resources and efforts towards the exploration of novel therapeutic options. This review aims to provide a comprehensive overview of the AD-related hypotheses, along with the computational approaches employed in research within each hypothesis. In this comprehensive review, the authors shed light on using various computational tools, including diverse case studies, in the pursuit of finding efficacious treatments for AD. The development of more sophisticated diagnostic techniques is crucial, enabling early detection and intervention in the battle against this challenging condition. The potential treatments investigated in this analysis are poised to assume ever more significant functions in both preventing and treating AD, ultimately enhancing the management of the condition and the overall well-being of individuals affected by AD.

UNASSIGNED: The importance of cerebrospinal fluid (CSF) biomarkers in Alzheimer\'s disease (AD) diagnosis is rapidly increasing, and there is a growing interest in the use of CSF biomarkers in monitoring the response to therapy, especially in the light of newly available approaches to the therapy of neurodegenerative diseases.
UNASSIGNED: In this review we discuss the most relevant measures of neurodegeneration that are being used to distinguish patients with AD from healthy controls and individuals with mild cognitive impairment, in order to provide an overview of the latest information available in the scientific literature. We focus on markers related to amyloid processing, markers associated with neurofibrillary tangles, neuroinflammation, neuroaxonal injury and degeneration, synaptic loss and dysfunction, and markers of α-synuclein pathology.
UNASSIGNED: In addition to neuropsychological evaluation, core CSF biomarkers (Aβ42, t-tau, and p-tau181) have been recommended for improvement of timely, accurate and differential diagnosis of AD, as well as to assess the risk and rate of disease progression. In addition to the core CSF biomarkers, various other markers related to synaptic dysfunction, neuroinflammation, and glial activation (neurogranin, SNAP-25, Nfl, YKL-40, TREM2) are now investigated and have yet to be validated for future potential clinical use in AD diagnosis.

Alzheimer\'s Disease (AD) is a progressive neurological disease associated with behavioral abnormalities, memory loss, and cognitive impairment that cause major causes of dementia in the elderly. The pathogenetic processes cause complex effects on brain function and AD progression. The proper protein homeostasis, or proteostasis, is critical for cell health. AD causes the buildup of misfolded proteins, particularly tau and amyloid-beta, to break down proteostasis, such aggregates are toxic to neurons and play a critical role in AD pathogenesis. The rise of cellular senescence is accompanied by aging, marked by irreversible cell cycle arrest and the release of pro-inflammatory proteins. Senescent cell build-up in the brains of AD patients exacerbates neuroinflammation and neuronal degeneration. These cells senescence-associated secretory phenotype (SASP) also disturbs the brain environment. When proteostasis failure and cellular senescence coalesce, a cycle is generated that compounds each other. While senescent cells contribute to proteostasis breakdown through inflammatory and degradative processes, misfolded proteins induce cellular stress and senescence. The principal aspects of the neurodegenerative processes in AD are the interaction of cellular senescence and proteostasis failure. This review explores the interconnected roles of proteostasis disruption and cellular senescence in the pathways leading to neurodegeneration in AD.

UNASSIGNED: Down syndrome (DS) is one of the most commonly occurring chromosomal conditions. Most individuals with DS develop Alzheimer\'s disease (AD) by 50 years of age. Recent evidence suggests that AD pathology in the locus coeruleus (LC) is an early event in sporadic AD. It is likely that the widespread axonal network of LC neurons contributes to the spread of tau pathology in the AD brain, although this has not been investigated in DS-AD.
UNASSIGNED: The main purpose of this study was to profile AD pathology and neuroinflammation in the LC, comparing AD and DS-AD in postmortem human tissues.
UNASSIGNED: We utilized immunofluorescence and semi-quantitative analyses of pTau (4 different forms), amyloid-β (Aβ), glial, and neuronal markers in the LC across 36 cases (control, DS-AD, and AD) to compare the different pathological profiles.
UNASSIGNED: Oligomeric tau was highly elevated in DS-AD cases compared to LOAD or EOAD cases. The distribution of staining for pT231 was elevated in DS-AD and EOAD compared to the LOAD group. The DS-AD group exhibited increased Aβ immunostaining compared to AD cases. The number of tau-bearing neurons was also significantly different between the EOAD and DS-AD cases compared to the LOAD cases.
UNASSIGNED: While inflammation, pTau, and Aβ are all involved in AD pathology, their contribution to disease progression may differ depending on the diagnosis. Our results suggest that DS-AD and EOAD may be more similar in pathology than LOAD. Our study highlights unique avenues to further our understanding of the mechanisms governing AD neuropathology.

UNASSIGNED: With the advent of anti-β-amyloid therapies, clinical distinction between Aβ + and Aβ- in cognitive impairment is becoming increasingly important for stratifying referral and better utilization of biomarker assays.
UNASSIGNED: Cognitive profile, rate of decline, neuropsychiatric inventory questionnaire (NPI-Q), and imaging characteristics were collected from 52 subjects with possible/probable AD.
UNASSIGNED: Participants with Aβ+ status had lower baseline MMSE scores (24.50 vs. 26.85, p = 0.009) and higher total NPI-Q scores (2.73 vs. 1.18, p < 0.001). NPI-Q score was found to be the only independent predictor for β-amyloid positivity (p = 0.008). A simple scoring system, namely Clinical β-Amyloid Positivity Prediction Score (CAPS), was developed by using the following parameters: NPI-Q, rapidity of cognitive decline, and white matter microangiopathy. Data from 48 participants were included in the analysis of accuracy of CAPS. CAP Score of 3 or 4 successfully classified Aβ + individuals in 86.7% cases.
UNASSIGNED: Clinical β-Amyloid Positivity Prediction Score is a simple clinical tool for use in primary care and memory clinic settings to predict β-amyloid positivity in individuals with clinical Alzheimer Syndrome can potentially facilitate referral for Anti Aβ therapies.

Alzheimer\'s disease (AD) is the most common neurodegenerative disorder in the aging population. An accumulation of amyloid plaques and neurofibrillary tangles causes degeneration of neurons, leading to neuronal cell death. The anthocyanin-rich fraction of black rice (Oryza sativa L. variety \"Luem Pua\") bran (AFBRB), extracted using a solution of ethanol and water and fractionated using Amberlite XAD7HP column chromatography, contains a high anthocyanin content (585 mg of cyanidin-3-O-glucoside and 24 mg of peonidin-3-O-glucoside per gram of the rich extract), which has been found to reduce neurodegeneration. This study focused on the neuroprotective effects of AFBRB in Aβ25-35-induced toxicity in the human neuroblastoma cell line (SK-N-SH). SK-N-SH was exposed to Aβ25-35 (10 µM) to induce an AD cell model in vitro. Pretreatment with AFBRB (0.1, 1, or 10 µg/mL) or C3G (20 µM) was conducted for 2 h prior to the treatment with Aβ25-35 (10 µM) for an additional 24 h. The results indicate that AFBRB can protect against the cytotoxic effect of Aβ25-35 through attenuation of intracellular ROS production, downregulation of the expression of the proteins Bax, cytochrome c, cleaved caspase-9, and cleaved caspase-3, upregulation of the expression of Bcl-2 in the mitochondrial death pathway, and reduction in the expression of the three major markers of ER stress pathways in similar ways. Interestingly, we found that pretreatment with AFBRB significantly alleviated Aβ-induced oxidative stress, ER stress, and apoptosis in SK-N-SH cells. This suggests that AFBRB might be a potential therapeutic agent in preventing neurodegenerative diseases.

Alzheimer\'s disease (AD) remains the foremost cause of dementia and represents a significant unmet healthcare need globally. The complex pathogenesis of AD, characterized by various pathological and physiological events, has historically challenged the development of anti-AD drugs. However, recent breakthroughs in AD drug development, including the approvals of aducanumab, lecanemab, and sodium oligomannate (GV-971), have ended a nearly two-decade hiatus in the introduction of new AD drugs. These developments have addressed long-standing challenges in AD drug development, marking a substantial shift in the therapeutic landscape of AD. Moreover, natural products (NPs) have shown promise in AD drug research, with several currently under clinical investigation. Their distinct properties and mechanisms of action offer new avenues to complement and enhance existing AD treatment approaches. This review article aims to provide an overview of the recent advancements and prospects in AD therapeutics, focusing on both NPs and approved drugs.

Brain organoids have become a valuable tool for studying human brain development, disease modeling, and drug testing. However, generating brain organoids with mature neurons is time-intensive and often incomplete, limiting their utility in studying age-related neurodegenerative diseases such as Alzheimer\'s disease (AD). Here, we report the generation of 3D brain organoids from human fibroblasts through direct reprogramming, with simplicity, efficiency, and reduced variability. We also demonstrate that induced brain organoids from APOE ε4 AD patient fibroblasts capture some disease-specific features and pathologies associated with APOE ε4 AD. Moreover, APOE ε4-induced brain organoids with mutant APP overexpression faithfully recapitulate the acceleration of AD-related pathologies, providing a more physiologically relevant and patient-specific model of familial AD. Importantly, transcriptome analysis reveals that gene sets specific to APOE ε4 patient-induced brain organoids are highly similar to those of APOE ε4 post-mortem AD brains. Overall, induced brain organoids from direct reprogramming offer a promising approach for more efficient and controlled studies of neurodegenerative disease modeling.