Abstract Introduction Alzheimer’s disease is a neurocognitive disorder that affects elderly people by slowly impaired cognition, dementia, and gets worse with age. It slowly impacts the quality of life. Clinically, it is distinguished by a transition from episodic memory to a gradual reduction in cognitive ability leading to cognitive dysfunction. Neurofibrillary tangles and amyloid plaques are unique structures that are thought to have a role in the pathogenesis of Alzheimer's disease. In this review, we focus our attention on the risk factors, pathophysiology, etiology, epidemiology, stages, diagnosis, treatment, mechanisms, pathways, ongoing clinical trials data and risks potentially associated with the development of Alzheimer's disease. Short summary This review aims to extrapolate the information about Alzheimer's disease. Preliminary research was done by selecting reviews on PubMed, Elsevier, and Google open-access publications using the keywords like “Alzheimer, dementia, neurodegenerative, memory, amyloid β, mechanism of action, pathways”. Conclusion Here we show the discussion and interpretation of several signaling pathways in the pathogenesis of Alzheimer's disease such as amyloid β plaque cleavage, Metal ion hypothesis, amyloid β degradation, initiation of amyloidogenic and non-amyloidogenic pathway, oxidative stress hypothesis, Metabolic syndrome, insulin resistance and tau phosphorylation associated apolipoprotein- cholesterol, neurofibrillary tangles accumulation, and insulin resistance which are significant for better understanding of the disease initiation and progression. On studying the ongoing clinical trials, it was found that current drugs being tested are crenezumab, gantenerumab and sodium oligonucleotide. Graphical Abstract 

pdf/targeting-the-molecular-web-of-alzheimers-disease-unveiling-4x1rja2mz2.pdf

Targeting the molecular web of Alzheimer’s disease: unveiling pathways for effective pharmacotherapy

•PSEN2 variants are associated with various neurodegenerative disorders and phenotypes •Most variants cause Alzheimer's disease (AD) or Lewy body dementia (LB-D) •PSEN2 Ile149Thr variant can yield juvenile dystonia-parkinsonism with voiceless whispering stereotypies •At onset, PSEN2 Ile149Thr cognitive phenotype may resemble an atypical AD-PCA, in the advanced stage a LB-D spectrum •PSEN2 could act as a phenotypic modifier of complex neurodegenerative diseases 

Rare causes of dystonia-parkinsonism with cognitive impairment, behavioral abnormalities, and voiceless whispering stereotypies: Describing the long-term evolution of the neurological phenotype in a patient with the PSEN2 Ile149Thr variant

Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future.

/pdf/a-possible-pathogenic-psen2-gly56ser-mutation-in-a-korean-35z8ciq5.pdf

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Targeting histone lysine demethylase KDM4A in Aggressive Variant Prostate Cancer

Neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of prostate cancer (PCa) and lacks life-prolonging treatment. The incidence of NEPC is increased due to the widespread use of AR pathway inhibitors (ARPIs) in the treatment of non-metastatic CRPC and hormone-sensitive metastatic tumors. Here, we identified histone lysine demethylase KDM4A as a key player in NEPC progression and an effective therapeutic target. We found that KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Knockdown (KD) or knockout (KO) of KDM4A in NEPC cell lines suppressed cancer cell growth in vitro and in vivo. Mechanistically, we found that KDM4A promotes NEPC progression, in part, through direct transcriptional regulation of MYC. We showed that MYC is hyper-activated in human and mouse NEPC. KDM4A KD led to suppression of MYC signaling. MYC KD or inhibition profoundly suppressed NEPC cell proliferation. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduced NEPC cell growth in vitro and in vivo. Taken together, we demonstrated that KDM4A is an important regulator of NEPC progression and targeting KDM4A may potentially be an effective therapeutic strategy for NEPC. Significance Neuroendocrine prostate cancer (NEPC) is a highly aggressive prostate cancer subtype that is resistant to potent androgen receptor pathway inhibitors (ARPIs) and currently lacks effective therapeutic options. Histone lysine demethylase KDM4A is an important epigenetic regulator of gene expression in development and cancer. In this study, we show that KDM4A is highly expressed in NEPC and is required for NEPC proliferation, anchorage-independent growth, and in vivo growth, which is in part mediated through the regulation of MYC expression. Importantly, we demonstrate that inhibition of KDM4A significantly impairs NEPC growth in preclinical models. Thus, our findings provide valuable insights into the molecular mechanisms underlying NEPC progression and offer a rationale for clinical trials with KDM4 inhibitor in NEPC patients.

KDM4A promotes the progression of neuroendocrine prostate cancer

Yes-associated protein 1 (YAP1), a key transcriptional coactivator in the Hippo pathway, is an important driver in cancer development and progression (1). It plays an oncogenic role in various cancer types. However, multiple studies also support a tumor-suppressive function for YAP1 (2-8). Thus, the functions of YAP1 are likely context-dependent (9). On the cellular level, YAP1 promotes prostate cancer cell proliferation (

Yap1 Hydroxylation Suppress Prostate Cancer Metastasis

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A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Targeting histone lysine demethylase KDM4A in Aggressive Variant Prostate Cancer

KDM4A promotes the progression of neuroendocrine prostate cancer

Yap1 Hydroxylation Suppress Prostate Cancer Metastasis