Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease

To test whether antibodies against beta-amyloid are effective in slowing progression of Alzheimer's disease, we assessed cognitive functions in 30 patients who received a prime and a booster immunization of aggregated Abeta(42) over a 1 year period in a placebo-controlled, randomized trial. Twenty patients generated antibodies against beta-amyloid, as determined by tissue amyloid plaque immunoreactivity assay. Patients who generated such antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, as indicated by the Mini Mental State Examination, the Disability Assessment for Dementia, and the Visual Paired Associates Test of delayed recall from the Wechsler Memory Scale, as compared to patients without such antibodies. These beneficial clinical effects were also present in two of three patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis. Our results establish that antibodies against beta-amyloid plaques can slow cognitive decline in patients with Alzheimer's disease.     

Increase of total homocysteine concentration in cerebrospinal fluid in patients with Alzheimer's disease and Parkinson's disease

We determined the concentrations of free homocysteine (HC) and total HC in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) or Parkinson's disease (PD) in order to elucidate whether HC is related to the pathogenesis of these neurodegenerative diseases. The concentration of free HC did not differ significantly from that of the normal controls, while the concentration of total HC was significantly higher in the AD and PD patients (+31% in AD,+31% in PD; p<0.05). These findings suggest that an increase of total HC concentration in the brain is commonly seen in patients with AD and PD, and this may be related to the pathogenesis of these two diseases.     

Synergetic analysis of spatio-temporal EEG patterns: Alzheimer's disease

 A spatio-temporal analysis has been employed on EEG signals recorded in groups of patients with Alzheimer's disease (AD). The so-called Karhunen–Loeve analysis method was applied to four groups of subjects: 12 patients who were diagnosed as having severe AD, 8 mild AD patients, 10 vascular dementia patients, and 10 normal aged controls, to obtain the spatio-temporal eigenpatterns. The local difference of the global EEG pattern in mild AD patients from that of normal controls was expanded to the frontal regions in the case of severe AD. The analysis showed significant bilateral temporal functioning differences and inter-hemispheric connection difficulty, along with remarkable intra-hemispheric correlation in severe AD patients. Compared to the normal controls, severe AD patients' brains exhibit only weak local connections and correlations, resulting into limited harmonious inter-hemispheric information processing. The results from the spatio-temporal EEG study of AD patients can be considered to be due to a change in the relative activity of the brain corresponding to the pathologic variation in AD, and the results are in accordance with reported clinical studies. Received: 3 March 2000 / Accepted in revised form: 8 January 2001     

Microglia modulation through external vagus nerve stimulation in a murine model of Alzheimer's disease

Chronically activated microglia contribute to the development of neurodegenerative diseases such as Alzheimer's disease (AD ) by the release of pro‐inflammatory mediators that compromise neuronal function and structure. Modulating microglia functions could be instrumental to interfere with disease pathogenesis. Previous studies have shown anti‐inflammatory effects of acetylcholine (AC h) or norepinephrine (NE ), which mainly activates the β‐receptors on microglial cells. Non‐invasive vagus nerve stimulation (nVNS ) is used in treatment of drug‐resistant depression, which is a risk factor for developing AD . The vagus nerve projects to the brainstem's locus coeruleus from which noradrenergic fibers reach to the Nucleus Basalis of Meynert (NBM ) and widely throughout the brain. Pilot studies showed first signs of cognitive‐enhancing effects of nVNS in AD patients. In this study, the effects of nVNS on mouse microglia cell morphology were analyzed over a period of 280 min by 2‐photon laser scanning in vivo microscopy. Total branch length, average branch order and number of branches, which are commonly used indicators for the microglial activation state were determined and compared between young and old wild‐type and amyloid precursor protein/presenilin‐1 (APP/PS1) transgenic mice. Overall, these experiments show strong morphological changes in microglia, from a neurodestructive to a neuroprotective phenotype, following a brief nVNS in aged animals, especially in APP/PS 1 animals, whereas microglia from young animals were morphologically unaffected.

     

Three apoptotic genes are upregulated in a patient with Alzheimer's disease and well-differentiated squamous cell carcinoma

We report the case of a 74-year-old man with Alzheimer's disease (AD) and an extensive ulcerative lesion on the right ear. AD is a neurodegenerative disease with progressive loss of memory and cognitive deterioration. It has been suggested that apoptotic cell injury and eventually cell death is a major contributor to the AD neurodegenerative process. The ulcerative lesion was surgically excised and the histological analysis reported a well-differentiated squamous cell carcinoma. Caspase-3 (CASP3) plays an important role in neuronal death during nervous system development and under certain pathological conditions. Furthermore, in vitro and in vivo studies reported elevated expression and activation of CASP3 in models of AD. Molecular epidemiological studies suggest that CASP3 may contribute to head and neck squamous cell carcinoma susceptibility and disease progression and that increased CASP3 expression is associated with tumors of the head. Also poly (ADP-ribose) polymerase 1 (PARP1) and the leucine zipper downregulated in cancer 1 (LDOC1) genes play a proapoptotic role. We therefore evaluated the differential expression of LDOC1, PARP1, and CASP3 mRNA in peripheral blood leukocytes of our patient. We found increased expression of all these genes compared with the expression in control subjects.     

Protective effects of positive lysosomal modulation in Alzheimer's disease transgenic mouse models

Alzheimer's disease (AD) is an age-related neurodegenerative pathology in which defects in proteolytic clearance of amyloid β peptide (Aβ) likely contribute to the progressive nature of the disorder. Lysosomal proteases of the cathepsin family exhibit up-regulation in response to accumulating proteins including Aβ(1-42). Here, the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK) was used to test whether proteolytic activity can be enhanced to reduce the accumulation events in AD mouse models expressing different levels of Aβ pathology. Systemic PADK injections in APP(SwInd) and APPswe/PS1ΔE9 mice caused 3- to 8-fold increases in cathepsin B protein levels and 3- to 10-fold increases in the enzyme's activity in lysosomal fractions, while neprilysin and insulin-degrading enzyme remained unchanged. Biochemical analyses indicated the modulation predominantly targeted the active mature forms of cathepsin B and markedly changed Rab proteins but not LAMP1, suggesting the involvement of enhanced trafficking. The modulated lysosomal system led to reductions in both Aβ immunostaining as well as Aβ(x-42) sandwich ELISA measures in APP(SwInd) mice of 10-11 months. More extensive Aβ deposition in 20-22-month APPswe/PS1ΔE9 mice was also reduced by PADK. Selective ELISAs found that a corresponding production of the less pathogenic Aβ(1-38) occurs as Aβ(1-42) levels decrease in the mouse models, indicating that PADK treatment leads to Aβ truncation. Associated with Aβ clearance was the elimination of behavioral and synaptic protein deficits evident in the two transgenic models. These findings indicate that pharmacologically-controlled lysosomal modulation reduces Aβ(1-42) accumulation, possibly through intracellular truncation that also influences extracellular deposition, and in turn offsets the defects in synaptic composition and cognitive functions. The selective modulation promotes clearance at different levels of Aβ pathology and provides proof-of-principle for small molecule therapeutic development for AD and possibly other protein accumulation disorders.     

Impaired modulation of GABAergic transmission by muscarinic receptors in a mouse transgenic model of Alzheimer's disease

It has long been recognized that muscarinic acetylcholine receptors (mAChRs) are crucial for the control of cognitive processes, and drugs that activate mAChRs are helpful in ameliorating cognitive deficits of Alzheimer's disease (AD). On the other hand, GABAergic transmission in prefrontal cortex (PFC) plays a key role in "working memory" via controlling the timing of neuronal activity during cognitive operations. To test whether the muscarinic and gamma-aminobutyric acid (GABA) system are interconnected in normal cognition and dementia, we examined the muscarinic regulation of GABAergic transmission in PFC of an animal model of AD. Transgenic mice overexpressing a mutant gene for beta-amyloid precursor protein (APP) show behavioral and histopathological abnormalities resembling AD and, therefore, were used as an AD model. Application of the mAChR agonist carbachol significantly increased the spontaneous inhibitory postsynaptic current (sIPSC) frequency and amplitude in PFC pyramidal neurons from wild-type animals. In contrast, carbachol failed to increase the sIPSC amplitude in APP transgenic mice, whereas the carbachol-induced increase of the sIPSC frequency was not significantly changed in these mutants. Similar results were obtained in rat PFC slices pretreated with the beta-amyloid peptide (Abeta). Inhibiting protein kinase C (PKC) blocked the carbachol enhancement of sIPSC amplitudes, implicating the PKC dependence of this mAChR effect. In APP transgenic mice, carbachol failed to activate PKC despite the apparently normal expression of mAChRs. These results show that the muscarinic regulation of GABA transmission is impaired in the AD model, probably due to the Abeta-mediated interference of mAChR activation of PKC.