Dementia is the progressive or chronic dysfunction of cortical or subcortical functions that results in complex cognitive decline and Alzheimer's disease is the most common etiology of dementia. Currently, causal genetic mutations such as amyloid precursor protein, presenilin 1, presenilin 2 in familial Alzheimer's disease and many susceptible genes including polymorphysm of apolipoprotein E have been reported. Furthermore, genetic testings are available in person at risk for Alzheimer's disease. However, besides from results of genetic testing, there are many issues such as economics, ethics, psychological and legal. So clinician should be considered these complexities before ordering genetic test for patients with/without Alzheimer's disease.
Alzheimer Disease ; Amyloid ; Apolipoproteins ; Dementia ; Genetic Testing ; Humans ; Presenilin-1 ; Presenilin-2

Alzheimer's disease (AD) is the most common senile neurodegenerative disease characterized by progressive cognitive dysfunction, psychological and behavioral abnormalities, and impaired ability of activities of daily living. A family with a total of 3 patients were admitted to the Department of Neurology of Xiangya Hospital, Central South University in 2018. The proband showed memory decline as the presenting symptoms, and subsequently showed psychological and behavioral abnormalities, personality changes, seizures, and motor retardation. Definite diagnosis of early-onset familial AD (EOFAD) with missense mutation of presenilin 2 (PSEN2) (c.715A>G p.M239V) was established by whole exome sequencing (WES) technology. We reported the mutation in Chinese Han population for the first time, which expanded the mutation spectrum ofPSEN2 gene and aid to enrich the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations. Patients with early onset age and complex clinical manifestations of AD can be diagnosed with the help of genetic testing to avoid misdiagnosis.
Activities of Daily Living ; Alzheimer Disease/genetics* ; Humans ; Mutation ; Neurodegenerative Diseases ; Presenilin-1/genetics* ; Presenilin-2/genetics*

Alzhelmer's disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing betaamylold (Abeta) derived from amyloid precursor protein (APP) and tau-rich neurofibrillary tangles. To date, the cause and progression of familial or sporadic AD have not been fully elucidated. About 10% of all cases of AD occur as autosomal dominant inherited forms of early-onset AD, which are caused by mutations in the genes encoding APP, presenilin-1 and presenilin-2. Proteolytic processing of APP by beta-gamma-secretase and caspase generates Abetaand carboxyl-terminal fragments of APP (APP-CTFs), which have been implicated in the pathogenesis of AD. The presenilins function as one of the gamma-secretases. Abetawhich is the main component of the amyloid plaques found, is known to exert neurotoxicity by accumulating free radicals, disturbing calcium homeostasis, evoking inflammatory response and activating signaling pathways. The CTFs have been found in AD patients' brain and reported to exhibit much greater neurotoxicity than Abeta. Furthermore CTFs are known to impair calcium homeostasis and learning and memory, triggering a strong inflammatory reaction through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction. Recently, it was reported that CTF translocated into the nucleus and in turn, affected transcription of genes including glycogen synthase kinase-3beta which results in the induction of tau-rich neurofibrillary tangles and subsequently cell death. One of the hallmarks of AD, neurofibrillary tangles (NFT), is formed by insoluble intracellular polymers of hyperphosphorylated tau that is believed to cause apoptosis by disrupting cytoskeletal and axonal transport. This review covers the processing of APP, toxic mechanisms of Abetaand CTFs of APP, presenilin and also tau in relation to the pathogenesis of AD.
Amyloid ; Apoptosis ; Axonal Transport ; Brain ; Calcium ; Cell Death ; Dementia* ; Free Radicals ; Gliosis ; Glycogen Synthase ; Homeostasis ; Learning ; Memory ; Neurofibrillary Tangles ; Plaque, Amyloid ; Polymers ; Presenilin-1 ; Presenilin-2 ; Presenilins

Apoptosis is a form of cell death in which the cells shrink and exhibit nuclear chromatin condensation and DNA fragmentation, and yet maintain membrane integrity. Many lines of evidence have shown that brain neurons are vulnerable to degeneration by apoptosis. Also it has been suggested that apoptosis is one of the mechanism contributing neuronal loss in Alzheimer's disease(AD), since the conditions in the disease(A beta peptide, oxidative stress, low energy metabolism) are the inducers that activate apoptosis. Indeed some neurons in vulnerable regions of the AD brain show DNA damage, chromatin condensation, and apoptic bodies. Consistently, mutations in AD causative genes(Amyloid precursor protein, Presenilin-1 and Presenilin-2) increase A beta peptide1-42(Abeta1-42) and sensitize neuronal cell to apoposis. However, several lines of evidence have shown that the location of neuronal loss and A beta peptide deposition is not correlated in AD brain and transgenic mice brain over-expressing Abeta1-42. Taken together, these data may indicated that A beta peptide(and other causative factors of AD) can interact with other cellular insults or risk factors to exacerbate pathological mechansim of AD through apoptosis. Thus, this review discusses possible role and mechanism of apoptosis in AD.
Alzheimer Disease* ; Amyloid beta-Peptides ; Animals ; Apoptosis* ; Brain ; Cell Death ; Chromatin ; DNA Damage ; DNA Fragmentation ; Membranes ; Mice ; Mice, Transgenic ; Neurons ; Oxidative Stress ; Presenilin-1 ; Presenilin-2 ; Risk Factors

Alzheimer's disease (AD) is known to induce alterations of mitochondrial function such as elevation of oxidative stress and activation of apopotosis. The aim of this study was to investigate the effects of human Presenilin 2 mutant (hPS2m) overexpression on the γ-secretase complex in the mitochondrial fraction. To achieve this, alterations of γ-secretase complex expression and activity were detected in the mitochondrial fraction derived from brains of NSE/hPS2m Tg mice and Non-Tg mice. Herein, the following were observed: i) overexpression of the hPS2m gene significantly up-regulated the deposition of Aβ-42 peptides in the hippocampus and cortex of brain, ii) overexpression of hPS2m protein induced alterations of γ-secretase components such as main component protein and activator protein but not stabilization-related proteins, iii) changes in γ-secretase components induced by overexpression of hPS2m protein up-regulated γ-secretase activity in the mitochondrial fraction, and iv) elevation of γ-secretase activity induced production of Aβ-42 peptides in the mitochondrial fraction. Based on these observations, these results indicate that alteration of γ-secretase activity in cells upon overexpression of hPS2m is tightly linked to mitochondrial dysfunction under the specific physiological and pathological conditions of AD.
Alzheimer Disease ; Animals ; Brain* ; Hippocampus ; Humans ; Mice ; Mice, Transgenic* ; Mitochondria* ; Oxidative Stress ; Peptides ; Presenilin-2 ; Presenilins* ; Up-Regulation*

OBJECTIVETo study the effect of Tiaoxin Recipe (TXR) on learning and memory related gene expression in hippocampus of senescence accelerated mice (SAM).

METHODSChanges of learning and memory related gene expression, including mineralocorticoid receptor (MR), presenile protein 1 and 2 (PS-1, PS-2), tau, APP, apoE and bcl-2 in hippocampus of SAM were determined by reverse transcription polymerase chain reaction (RT-PCR). The effect of TXR were tested. E2020 was used as the drug for control.

RESULTSCompared with those in the same aged mice, in the 5-month old SAM, levels of gene expression of MR, tau, PS-2 and APP were significantly higher, that of apo-E lower, levels of gene expression PS-1 and bcl-2 were unobviously changed; while in the 12-month old SAM, gene expression of MR and tau were higher, bcl-2 was lower and PS-1, PS-2, apoE and APP were also unobviously changed. Continuously orally taken TXR could correct the abnormality of MR, tau and apoE gene expression in hippocampus of 5-month SAM and that of MR and bcl-2 in 12-month SAM.

CONCLUSIONContinuously orally taken of TXR has the effect of regulating and correcting learning and memory related gene expression in hippocampus of 5-month and 12-month SAM.

Aging ; drug effects ; metabolism ; Animals ; Apolipoproteins E ; biosynthesis ; genetics ; Gene Expression ; Hippocampus ; metabolism ; Learning ; drug effects ; Membrane Proteins ; biosynthesis ; genetics ; Memory ; drug effects ; Mice ; Presenilin-1 ; Presenilin-2 ; tau Proteins ; biosynthesis ; genetics

BACKGROUNDThe aim of this study was to investigate DNA content and expression of c-erbB-2, PS2, and prostate-specific antigen (PSA) proteins in breast carcinomas with neuroendocrine (NE) cell differentiation.

METHODSChromogranin, c-erbB-2, PS2, and PSA in 131 samples of breast cancer were detected immunohistochemically. Classic Feulgen staining image analysis techniques were used to quantify DNA content in 81 of the breast cancer samples.

RESULTSThe c-erbB-2 positive rate in breast carcinoma samples containing neuroendocrine cells was 37.5% and the rate of high expression of c-erbB-2 (++ or +++) was 33.3%, both significantly lower than that in breast carcinomas without neuroendocrine cells (62.6% and 68.7%, respectively, P < 0.05). The rates of positive PS2 and PSA expression in breast carcinoma samples containing neuroendocrine cells were 72.2% and 55.0%, respectively, both significantly higher than that in breast carcinoma samples without neuroendocrine cells (45.0% and 16.4%, respectively, P < 0.05). In NE(+) samples, the integral optical density, DNA index, DNA stemline peak, > 5 c aneuploidy cells, and rate of aneuploidy among cells were all lower than that in NE(-) breast carcinomas (P < 0.01). In NE(+) grade I or II breast carcinomas, these indices were also all lower than that in the NE(-) breast carcinoma samples (P < 0.01).

CONCLUSIONBreast carcinomas with neuroendocrine differentiation have a lower rate of malignancy. Neuroendocrine differentiation could serve as a prognostic marker in clinical practice.

Breast Neoplasms ; chemistry ; pathology ; Cell Differentiation ; DNA ; analysis ; Female ; Humans ; Membrane Proteins ; analysis ; Neurosecretory Systems ; cytology ; Presenilin-2 ; Prostate-Specific Antigen ; analysis ; Receptor, ErbB-2 ; analysis

OBJECTIVETo detect the expressions of human epidermal growth factor receptor 2 (Her-2), epidermal growth factor receptor (EGFR), presenilin 2 (PS-2) and estrogen receptor (ER) in breast cancer and discuss their clinical implications.

METHODSThe expressions of Her-2, EGFR, PS-2 and ER were measured immunohistochemically in 108 patients with breast cancer.

RESULTSThe positive expression rates of Her-2, EGFR, PS-2 and ER were 37.0%, 40.7%, 57.4% and 53.7% respectively in the breast cancer patients. The expression of Her-2 was not correlated with EGFR, but inversely correlated with PS-2 and ER. The expressions of Her-2 and EGFR, PS-2, ER were correlated with the histological grades (P<0.05), and Her-2, EGFR and ER expressions with lymph node metastasis (P<0.05). The expressions of Her-2, EGFR, PS-2 and ER did not correlate to the pathological types, patient's age and tumor size (P>0.05).

CONCLUSIONExpressions of Her-2 and EGFR often suggests an unfavorable prognosis while expressions of PS-2 and ER suggest a more favorable one. Expressions of Her-2, EGFR, PS-2 and ER are useful prognostic factors in breast cancer patients.

Adult ; Aged ; Biomarkers, Tumor ; biosynthesis ; Breast Neoplasms ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; Female ; Humans ; Immunohistochemistry ; Middle Aged ; Presenilin-2 ; biosynthesis ; Prognosis ; Receptor, Epidermal Growth Factor ; biosynthesis ; Receptor, ErbB-2 ; biosynthesis ; Receptors, Estrogen ; biosynthesis

OBJECTIVEThis report aims to describe the oxidative damage profile in brain of presenilin1 and presenilin2 conditional double knockout mice (dKO) at both early and late age stages, and to discuss the correlation between oxidative stress and the Alzheimer-like phenotypes of dKO mice.

METHODSThe protein level of Abeta(42) in dKO cortex and free 8-OHdG level in urine were measured by ELISA. Thiobarbituric acid method and spectrophotometric DNPH assay were used to determine the lipid peroxidation and protein oxidation in cortex, respectively. SOD and GSH-PX activities were assessed by SOD Assay Kit-WST and GSH-PX assay kit, separately.

RESULTSSignificant decrease of Abeta(42) was verified in dKO cortex at 6 months as compared to control mice. Although lipid peroxidation (assessed by MDA) was increased only in dKO cortex at 3 months and protein oxidation (assessed by carbonyl groups) was basically unchanged in dKO cortex, ELISA analysis revealed that free 8-OHdG, which was an indicator of DNA lesion, was significantly decreased in urine of dKO mice from 3 months to 12 months. Activities of SOD and GSH-PX in dKO and control cortices showed no statistical difference except a significant increase of GSH-PX activity in dKO mice at 9 months.

CONCLUSIONOxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Abeta(42). Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.

Age Factors ; Alzheimer Disease ; genetics ; metabolism ; physiopathology ; Amyloid beta-Peptides ; urine ; Animals ; Deoxyguanosine ; analogs & derivatives ; urine ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; methods ; Glutathione ; metabolism ; Hydrazines ; metabolism ; Lipid Peroxidation ; genetics ; Malondialdehyde ; metabolism ; Mice ; Mice, Inbred CBA ; Mice, Knockout ; physiology ; Oxidation-Reduction ; Oxidative Stress ; physiology ; Peptide Fragments ; urine ; Presenilin-1 ; deficiency ; Presenilin-2 ; deficiency ; Spectrophotometry, Atomic ; methods ; Superoxide Dismutase ; metabolism

Alzheimer's disease (AD) is the most common cause of dementia in elderly population. There are two hallmark pathological lesions: the intracellular neurofibrillary tangles (NFTs) and the extracellular amyloid deposits in the senile plaques (SP). The NFTs are aggregates of hyperphosphorylated microtubule Tau protein. The amyloid deposits in the SP are the beta-amyloid (Abeta) peptides-Abeta40 and Abeta42. The Abeta peptides are derived from the amyloid precursor protein (APP) which is considered very important for the AD pathogenesis. In recent years, studies have focused on understanding the generation of Abeta peptides by the alpha-, beta- and gamma- secretase activity on APP, as cause and progression of both familial and sporadic AD (FAD and SAD). This review covers the trafficking and processing of APP, the amyloid cascade hypothesis in AD pathogenesis, the mutations in the genes encoding APP, PS1 and PS2 of early-onset and late-onset AD. The risk factor apolipoprotein E (ApoE) for AD and therapeutic anti-beta-amyloid vaccination strategies for prevention of AD are also discussed.
Alzheimer Disease ; genetics ; metabolism ; pathology ; therapy ; Alzheimer Vaccines ; immunology ; Amyloid beta-Peptides ; antagonists & inhibitors ; genetics ; immunology ; metabolism ; Amyloid beta-Protein Precursor ; genetics ; metabolism ; Animals ; Apolipoproteins E ; genetics ; Humans ; Immunotherapy, Active ; Membrane Proteins ; genetics ; Peptide Fragments ; genetics ; Plaque, Amyloid ; pathology ; Presenilin-1 ; Presenilin-2