Clinical characterization of a presenilin 1 mutation (F177S) in a family with very early-onset Alzheimer's disease in the third decade of life.

BACKGROUND: Early-onset familial Alzheimer disease (AD) is an autosomal dominant disorder caused by mutations in the amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 gene. The objective of this study was to characterize the phenotype in a large family with a PSEN1 F177S mutation by performing detailed clinical assessments, neuroimaging, and neuropathological analysis. METHODS: In two subjects, clinical and neuropsychological assessments, structural magnetic resonance imaging, F-18-2-fluoro-2-deoxy-D-glucose positron emission tomographic imaging, AD biomarkers in cerebrospinal fluid and genetic analysis were available. In three deceased affected subjects, medical records were reviewed. In one subject, a complete neuropathological examination was available. RESULTS: Cognitive impairment and neurological symptoms developed homogeneously around 30 years of age and worsened rapidly. All subjects died about 7 years (range, 6-8 years) after disease onset before 40 years of age. All technical diagnostic information (neuroimaging, cerebrospinal fluid) were typically for AD. Neuropathology showed abundant neuritic plaques and neurofibrillary tangles, typical of severe AD. Antidementia treatment in one subject did not alter the length of survival. CONCLUSIONS: The PSEN1 F177S mutation leads to typical AD starting at age 30 and a homogeneous phenotype with rapid cognitive decline and prominent neurological symptoms. Excessive amyloid beta 42 production in the brain cortex corresponds well with other PSEN1 mutations.

Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin.

Amyloid beta peptide (Abeta) has a key role in the pathological process of Alzheimer's disease (AD), but the physiological function of Abeta and of the amyloid precursor protein (APP) is unknown. Recently, it was shown that APP processing is sensitive to cholesterol and other lipids. Hydroxymethylglutaryl-CoA reductase (HMGR) and sphingomyelinases (SMases) are the main enzymes that regulate cholesterol biosynthesis and sphingomyelin (SM) levels, respectively. We show that control of cholesterol and SM metabolism involves APP processing. Abeta42 directly activates neutral SMase and downregulates SM levels, whereas Abeta40 reduces cholesterol de novo synthesis by inhibition of HMGR activity. This process strictly depends on gamma-secretase activity. In line with altered Abeta40/42 generation, pathological presenilin mutations result in increased cholesterol and decreased SM levels. Our results demonstrate a biological function for APP processing and also a functional basis for the link that has been observed between lipids and Alzheimer's disease (AD).

Functional consequences of the lack of amyloid precursor protein in the mouse dentate gyrus in vivo.

The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer's disease. Here, we studied whether the lack of APP affects the synaptic properties in the dentate gyrus by measuring granule cell field potentials evoked by perforant path stimulation in anesthetized 9-11-month-old APP-deficient mice in vivo. We found decreased paired-pulse facilitation, indicating altered presynaptic short-term plasticity in the APP-deficient dentate gyrus. In contrast, excitatory synaptic strength and granule cell firing were unchanged in APP knockout mice. Likewise, long-term potentiation (LTP) induced by a theta-burst stimulation protocol was not impaired in the absence of APP. These findings suggest that the deletion of APP may affect presynaptic plasticity of synaptic transmission at the perforant path-granule cell synapse but leaves synaptic efficacy intact and LTP preserved, possibly due to functional redundancy within the APP gene family.

Vaccination with Abeta-displaying virus-like particles reduces soluble and insoluble cerebral Abeta and lowers plaque burden in APP transgenic mice.

In transgenic animal models, humoral immunity directed against the beta-amyloid peptide (Abeta), which is deposited in the brains of AD patients, can reduce Abeta plaques and restore memory. However, initial clinical trials using active immunization with Abeta1-42 (plus adjuvant) had to be stopped as a subset of patients developed meningoencephalitis, likely due to cytotoxic T cell reactions against Abeta. Previously, we demonstrated that retrovirus-like particles displaying on their surface repetitive arrays of self and foreign Ags can serve as potent immunogens. In this study, we generated retrovirus-like particles that display the 15 N-terminal residues of human Abeta (lacking known T cell epitopes) fused to the transmembrane domain of platelet-derived growth factor receptor (Abeta retroparticles). Western blot analysis, ELISA, and immunogold electron microscopy revealed efficient incorporation of the fusion proteins into the particle membrane. Without the use of adjuvants, single immunization of WT mice with Abeta retroparticles evoked high and long-lived Abeta-specific IgG titers of noninflammatory Th2 isotypes (IgG1 and IgG2b) and led to restimulatable B cell memory. Likewise, immunization of transgenic APP23 model mice induced comparable Ab levels. The CNS of immunized wild-type mice revealed neither infiltrating lymphocytes nor activated microglia, and no peripheral autoreactive T cells were detectable. Importantly, vaccination not only reduced Abeta plaque load to approximately 60% of controls and lowered both insoluble Abeta40 as well as Abeta42 in APP23 brain, but also significantly reduced cerebral soluble Abeta species. In summary, Abeta retroparticle vaccination may thus hold promise as a novel efficient future candidate vaccine for active immunotherapy of Alzheimer's disease.

sAPPalpha antagonizes dendritic degeneration and neuron death triggered by proteasomal stress.

Impaired proteasomal function is a major hallmark in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). Here we investigated the biological properties of the secreted cleavage product of APP (sAPPalpha) in antagonizing stress signalling, dendritic degeneration and neuronal cell death induced by the proteasome inhibitor epoxomicin. Analysis of executioner caspase activation demonstrated that sAPPalpha was able to protect PC12 cells from apoptosis triggered by epoxomicin, as well as by genotoxic stress (UV irradiation). This anti-apoptotic effect of sAPPalpha was associated with inhibition of the stress-triggered c-Jun N-terminal kinase (JNK)-signalling pathway. The anti-apoptotic effect of sAPPalpha could also be confirmed in organotypic slice cultures of Thy1-GFP mouse hippocampi. Confocal time-lapse imaging of CA1 pyramidal neurons revealed that preincubation with sAPPalpha preserves the structural integrity of neurons after epoxomicin treatment. Taken together, our data demonstrate that sAPPalpha is neuroprotective under conditions of proteasomal stress.

beta-amyloid precursor protein can be transported independent of any sorting signal to the axonal and dendritic compartment.

In neurons, amyloid precursor protein (APP) is localized to the dendritic and axonal compartment. Changes in subcellular localization affect secretase cleavage of APP, altering the generation of Abeta, and presumably also its pathogenic features. It was reported that APP is sorted initially to the axon and transcytosed subsequently to the somatodendritic compartment. This may be carried out by a recessive dendritic sorting signal in the cytoplasmic C-terminus, possibly the tyrosine based basolateral sorting signal (BaSS), and an axonal sorting motif within the extracellular juxtamembraneous domain. We investigated whether the C- or N-terminal domain of APP contains an independent dendritic or axonal sorting signal. We generated different APP deletion mutants, and produced chimeric proteins of APP and a non-related Type I transmembrane protein. Quantitative immunocytochemical analyses of transfected primary neurons showed that similar amounts of all APP mutants, lacking either the N- or C-terminus, were transported to the axonal and dendritic compartment. Investigations of the chimeric proteins showed that neither the N- nor the C-terminus of APP functions as independent sorting signal, whereas another tyrosine based dendritic sorting signal was sufficient to prevent axonal entry of APP. This data shows that, under steady state conditions, Heterologously expressed APP is transported equally to axons and dendrites irrespective of any putative sorting signal in its N- or C-terminus. This shows that APP can enter the axon in absence of the initial axonal sorting motif, indicating the existence of an alternative pathway allowing axonal entry of APP.

Therapeutic perspectives in Alzheimer's disease.

It is now almost a century ago that Alois Alzheimer first presented his results in public. Main characteristics of Alzheimer's disease (AD) are massive cerebral accumulation of amyloid, composed of fibrillary aggregates of the Amyloid beta peptide (Abeta) and intracellular accumulation of abnormally phosphorylated tau protein associated with widespread neurodegeneration. The clinical picture is characterized by progressive and irreversible dementia, which is eventually fatal. To date, there is no cure for this severe disease affecting more than of 30 million individuals worldwide. In the last decades, the treatment of Alzheimer patients was mainly focusing on symptomatical strategies. Based on the augmented knowledge about the mechanisms underlying the pathology of AD, particularly the molecular causes and consequences of AD, different therapeutic approaches arose and recently, treatment with Statins, NSAIDs and Abeta vaccines reached the level of clinical trials, showing some indication of efficacy already. According to actual evaluations, these approaches have realistic chances to become established as therapeutic routine in AD within the next 10 years. We will review here some of the most promising novel approaches to cure and prevent rather than to treat the symptoms of AD.