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At least 649 records · Page 36Linked to original sources
PubMed1998

Amyloid-beta-protein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer disease.

To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Abeta peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Abeta peptide such as Abeta1-42(43) and Abetax-42(43). This enhancing effect of PS1 mutation on Abetax-42(43) deposition was highly similar to that of a betaAPP mutation (Val717Ile) but the effects on Abetax-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Abeta in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Abetax-40 peptides in brain of subjects with PS1 mutations.

Adult↗
PubMedDate not supplied

Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS1 mice.

Doubly transgenic mAPP+mPS1 mice (15-16 months) had impaired cognitive function in a spatial learning and memory task that combined features of a water maze and a radial arm maze. Nontransgenic mice learned a new platform location each day during 4 consecutive acquisition trials, and exhibited memory for this location in a retention trial administered 30 min later. In contrast, transgenic mice were, on average, unable to improve their performance in finding the hidden platform over trials. The cognitive performance of individual mice within the transgenic group were inversely related to the amount of Abeta deposited in the frontal cortex and hippocampus. These findings imply that mAPP+mPS1 transgenic mice develop deficits in cognitive ability as Abeta deposits increase. These data argue that radial arm water maze testing of doubly transgenic mice may be a useful behavioral endpoint in evaluating the functional consequences of potential AD therapies, especially those designed to reduce Abeta load.

Alzheimer Disease↗
PubMedDate not supplied

Reduced effectiveness of Abeta1-42 immunization in APP transgenic mice with significant amyloid deposition.

Vaccinations with Abeta1-42 have been shown to reduce amyloid burden in transgenic models of Alzheimer's disease (AD). We have further tested the efficacy of Abeta1-42 immunization in the Tg2576 mouse model of AD by immunizing one group of mice with minimal Abeta deposition, one group of mice with modest Abeta deposition, and one group with significant Abeta deposition. The effects of immunization on Abeta deposition were examined using biochemical and immunohistochemical methods. In Tg2576 mice immunized prior to significant amyloid deposition, Abeta1-42 immunization was highly effective. Biochemically extracted Abeta40 and Abeta42 levels were significantly reduced and immunohistochemical plaque load was also reduced. Immunization of mice with modest amounts of pre-existing Abeta deposits selectively reduced Abeta42 without altering Abeta40, although plaque load was reduced. In contrast, in Tg2576 mice with significant pre-existing Abeta loads, Abeta1-42 immunization only minimally decreased Abeta42 levels, whereas no alteration in Abeta40 levels or in plaque load was observed. These results indicate that in Tg2576 mice, Abeta1-42 immunization is more effective at preventing additional Abeta accumulation and does not result in significant clearance of pre-existing Abeta deposits.

Age Factors↗
PubMedDate not supplied

Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice.

Chronic expression of inflammatory cytokines, including interleukin-1beta, tumor necrosis factor alpha, and interleukin-6, by glia may underlie the neurodegenerative events that occur within the brains of patients with Alzheimer's disease (AD). The present study determined whether these markers of inflammation could be observed within the brains of Tg(HuAPP695.K670N/M671L)2576 transgenic mice (Tg2576) that have recently been shown to mimic many features of AD. Interleukin-1beta- and tumor necrosis factor alpha-immunopositive microglia were localized with thioflavine-positive (fibrillar) Abeta deposits. Moreover, interleukin-6 immunoreactive astrocytes surrounded fibrillar Abeta deposits. These findings provide evidence that Tg2576 mice exhibit features of the inflammatory pathology seen in AD and suggest that these mice are a useful animal model for studying the role inflammation may play in this disease.

Aging↗
PubMed2001

Abeta amyloidosis induces the initial stage of tau accumulation in APP(Sw) mice.

To clarify how Abeta deposits induce secondary tauopathy, the presence of phosphorylated tau, glycogen synthase kinase 3alpha (GSK3alpha), GSK3beta, cyclin-dependent kinase 5 (CDK5), mitogen-activated protein kinase (MAPK) and fyn were examined in the Tg2576 brain showing substantial brain Abeta amyloidosis and behavioral abnormalities. Phosphorylated tau at Ser199, Thr231/Ser235, Ser396 and Ser413 accumulated in the dystrophic neurites of senile plaques. The major kinase for tau phosphorylation was GSK3beta. Smaller contributions of GSK3alpha, CDK5 and MAPK were suggested. Thus, brain Abeta amyloidosis has a potential role in the induction of tauopathy leading to the mental disturbances of Alzheimer's disease.

Alzheimer Disease↗
PubMed1997

Further evidence for an association between a mutation in the APP gene and Lewy body formation.

There have been two detailed neuropathological reports of families with a valine to isoleucine substitution at position 717 of the amyloid precursor protein gene. Surprisingly, in one of these families substantial Lewy body formation occurred in addition to Alzheimer's disease, prompting the speculation that such a genetic mutation may predispose to both Lewy body and plaque formation. This report describes the neuropathology of an additional family with the same genetic mutation. Of two affected members who have come to autopsy, one had brainstem Lewy bodies. Some of these Lewy bodies had peripheral halos immunoreactive for beta-amyloid. These findings suggest a greater than chance link between genetic mutations for Alzheimer's disease and Lewy body formation.

Alzheimer Disease↗
PubMed2001

APP processing and synaptic plasticity in presenilin-1 conditional knockout mice.

We have developed a presenilin-1 (PS1) conditional knockout mouse (cKO), in which PS1 inactivation is restricted to the postnatal forebrain. The PS1 cKO mouse is viable and exhibits no gross abnormalities. The carboxy-terminal fragments of the amyloid precursor protein differentially accumulate in the cerebral cortex of cKO mice, while generation of beta-amyloid peptides is reduced. Expression of Notch downstream effector genes, Hes1, Hes5, and Dll1, is unaffected in the cKO cortex. Although basal synaptic transmission, long-term potentiation, and long-term depression at hippocampal area CA1 synapses are normal, the PS1 cKO mice exhibit subtle but significant deficits in long-term spatial memory. These results demonstrate that inactivation of PS1 function in the adult cerebral cortex leads to reduced Abeta generation and subtle cognitive deficits without affecting expression of Notch downstream genes.

Alzheimer Disease↗
PubMed2002

APP on the move.

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Alzheimer Disease↗
PubMed2002

The beta-amyloid precursor protein (APP) and Alzheimer's disease: does the tail wag the dog?

The beta-amyloid precursor protein has been the focus of much attention from the Alzheimer's disease community for the past decade and a half. The beta-amyloid precursor protein holds a pivotal position in Alzheimer's disease research because it is the precursor to the amyloid beta-protein which many believe plays a central role in Alzheimer's disease pathogenesis. It was also the first gene in which mutations associated with inherited Alzheimer's disease were found. Although the molecular details of the generation of amyloid beta-protein from beta-amyloid precursor protein are being unraveled, the actual physiological functions of beta-amyloid precursor protein are far from clear. This situation is changing as accumulating new evidence suggests that the C-terminal cytosolic tail of beta-amyloid precursor protein may have multiple biological activities, ranging from axonal transport to nuclear signaling. This article reviews the current state of knowledge about the biological functions of beta-amyloid precursor protein.

Alzheimer Disease↗
PubMed1994

Gelatinase A and APP.

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Amyloid Precursor Protein Secretases↗
PubMed1996

Looking for the DNA killer app.

The structural and functional properties of nucleic acids may form the basis for carrying out elementary and complex computational operations with biological molecules. A recent meeting on computing with DNA explored the potential of this approach.

Computers↗