Progress on loss-of-function hypothesis of presenilin-1 mutations in Alzheimer diseases / 浙江大学学报·医学版

Alzheimer's disease (AD) is an aging-related neurodegenerative disease and is associated with the accumulation of amyloid-β (Aβ) peptides in patient brains. AD can be classified into the familial type and sporadic type. () is the major risk gene for familial AD (fAD) because its mutations comprised over 80%of the total mutations causing fAD. PS1 is the catalytic subunit of the enzyme γ-secretase, which is responsible for the proteolytic cleavage of amyloid precursor protein (APP) to produce Aβ. Although novel fAD-causing mutations in PS1 are being reported increasingly, the molecular mechanisms underlying how these mutations induce fAD remain elusive. Since over 90%of the fAD-causing mutations in PS1 leads to a reduction of γ-secretase activity, the loss-of-function mutation hypothesis has been emerged, which suggests that the loss of PS1 functions may be the root cause of AD. Recently, increasing number of evidence supports this hypothesis. First, loss-of-function mutations increase the production of long-length Aβ by disturbing the cleavage sites of γ-secretase APP, thereby increasing the ratio of Aβ/Aβ; Second, loss-of-function mutations dysregulate endoplasmic reticulum calcium homeostasis in neurons; Third, loss-of-function mutations inhibit the autophagy activity of neurons, resulting in the abnormal accumulation of cleaved products from APP; Fourth, loss-of-function mutations alter the endocytosis and transcytosis processes in neurons, leading to neuratrophy; Fifth, loss-of-function mutations activate brain immune cells (astrocytes and microglia), which mount a strong neuroinflammation response; Last, loss-of-function mutations reduce the rates of glycolysis and the production of lactic acid, disrupting the balance of neuronal energy supply. In this article we summary the research progress on the loss-of-function hypothesis and pose several topics which would guide studies of this field in future.

Presenilins in dilated cardiomyopathy: An update / 第二军医大学学报

Presenilin (PS) is a transmembrane protein identified in familial early-onset Alzheimer disease, and it is mainly expressed in cell membranes and organelle membranes. As an important catalytic core of the γ-secretase multimeric enzyme complex, PS has been implicated in regulating various proteins. Recent researches have shown that mutations in PS are identified in the familial dilated cardiomyopathy, and the PS gene plays an important role in cardiac formation and regulation of calcium homeostasis in myocardial cells. In this review, we summarized the function of PS in heart and the mechanisms underlying the effects of PS on calcium homeostasis, such as amyloid β protein (Aβ), 1,4,5-inositol trisphosphate receptors, ryanodine receptors and PS as endoplasmic reticulum (ER) Ca2+ leak channels, hoping to provide a theoretical basis for the therapy of dilated cardiomyopathy.

Variation of Monoamine Neurotransmitter in Forebrain of Presenilin-1/Presenilin-2 Double Knockout Mice / 生物化学与生物物理进展

Conditional forebrain-specific presenilin-1 and presenilin-2 double knockout mice (dKO mice) exhibit several neurodegenerative phenotypes of Alzheimer's disease (AD) pathology, such as tau hyperphosphorylation, neuron loss, forebrain cortical shrinkage and memory impairment. By using capillary electrophoresis assay, monoamine neurotransmitters in forebrain cortex, hippocampus and other forebrain region of dKO mice aged at 6, 9 and 12 months were measured to illustrate the relationship among presenilins function deficiency, neurodegenerative phenotypes and monoamine neurotransmitters. Data showed that levels of monoamine neurotransmitters in forebrain cortex of dKO mice were significantly decreased at 6 months when compared to controls, while as mice getting older, levels of monoamine neurotransmitters increased to that of controls, or even higher. In hippocampus, 5-hydroxytryptamin and epinephrine in dKO mice had a significant increase at 6 months, followed with a significant increase of each monoamine neurotransmitter at 12 months age. In other forebrain region, 5-hydroxytryptamin and dopamine had a similar level between control and dKO mice at 6 and 9 months but a significant decrease at 12 months; however, level of norepinephrine and epinephrine were significantly decreased at 6 and 12 months except epinephrine of 6 months. These results demonstrated that knockout of presenilins genes could lead to the variation of monoamine neurotransmitters, and the variation profiles were different among forebrain cortex, hippocampus and other forebrain region. However, whether presenilins deficiency caused the variation of monoamine neurotransmitter directly or not, and how about the effects of variation of monoamine neurotransmitters on AD-like pathology need to be further analyzed.

Influência genética sobre a doença de Alzheimer de início precoce / Genetic influence on early onset Alzeimer's disease

CONTEXTO: A doença de Alzheimer de início precoce (DAIP) representa 5 por cento de todos os casos de doença de Alzheimer e está relacionada a mutações gênicas. OBJETIVO: Apresentar a influência de mutações gênicas na DAIP. MÉTODOS: Revisão da literatura, a partir de 1992, empregando o banco de dados PubMed. RESULTADOS: O alelo E*4 do gene da apolipoproteína E interfere na DAIP. No gene da proteína precursora da amiloide, foram descritas 20 mutações, que causam cerca de 10 por cento a 15 por cento dos casos de DAIP. Mutações no gene das presenilinas 1 e 2 causam 30 por cento a 70 por cento dos casos de DAIP. No gene da PSN1, há 30 mutações de troca de aminoácidos e três inserções/deleções. O gene da PSEN2 apresenta seis mutações de troca de aminácidos. No gene MAPT, apenas uma mutação se relaciona exclusivamente com a DA. CONCLUSÕES: O uso de informações genéticas para a detecção precoce de possíveis pacientes com DAIP ainda é bastante limitado. A heterogeneidade genética é ampla. Algumas mutações descritas nesta revisão foram responsáveis pela doença de Alzheimer em apenas algumas poucas famílias. A aplicação clínica desses métodos no rastreamento de indivíduos em risco para a DAIP ainda exige cautela.

BACKGROUND: Early onset Alzheimer's disease (EOAD) represents 5 percent of all cases of Alzheimer's disease, and it is connected to genic mutations. OBJECTIVES: To present the influence of genic mutations in EOAD. METHODS: Review of current literature, starting from 1992, utilizing the PubMed data bank. RESULTS: The E*4 allele of the apolipoprotein E gene interferes in EOAD. In the gene of the Amyloid Precursor Protein, 20 mutations were described, causing 10 percent to 15 percent of the cases of EOAD. Mutations in the gene of presenilins 1 and 2 cause 30 percent to 70 percent of the cases of EOAD. In PSN1 gene, 30 aminoacid change mutations and 3 insertions/deletions are known. In the PSEN2 gene, there are 6 aminoacid change mutations. Only one mutation in the MAPT gene is selectively associated with Alzheimer's disease. CONCLUSIONS: The use of genetic information for early detection of possible pacients of EOAD is still very limited. Genetic heterogeneity is broad. Some mutations described in this review were responsible for Alzheimer's disease only in a few families. The clinical utilization of these methods for screening individuals at risk for EOAD still asks for caution.