Search tips
Search criteria

Results 1-5 (5)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Stable Size Distribution of Amyloid Plaques Over the Course of Alzheimer Disease 
Amyloid-β plaques are a key pathological feature of Alzheimer disease (AD), but whether plaque sizes increase or stabilize over the course of AD is unknown. We measured the size distribution of total immunoreactive (10D5-positive) and dense-core (Thioflavine-S-positive) plaques in the temporal neocortex of a large group of AD and plaque-bearing age-matched non-demented subjects to test the hypothesis that amyloid plaques continue to grow along with the progression of the disease. The size of amyloid-β (10D5)-positive plaques did not differ between groups whereas dense-core plaques from the AD group were slightly larger than those in the non-demented group (~25%–30%, p = 0.01). Within the AD group, dense-core plaque size did not independently correlate with duration of clinical disease (from 4 to 21 years, p = 0.68), whereas 10D5-positive plaque size correlated negatively with disease duration (p = 0.01). By contrast, an earlier age of symptom onset strongly predicted a larger postmortem plaque size; this effect was independent of disease duration and the presence of the APOEε4 allele (p = 0.0001). We conclude that plaques vary in size among patients, with larger size distributions correlating with an earlier age of onset, but plaques do not substantially increase in size over the clinical course of the disease.
PMCID: PMC3407299  PMID: 22805771
Alzheimer disease; Amyloid plaques; APOE genotype; Dense-core plaques; Plaque growth; Plaque size
2.  T cell mediated cerebral hemorrhages and microhemorrhages during passive Aβ immunization in APPPS1 transgenic mice 
Immunization against amyloid-β (Aβ), the peptide that accumulates in the form of senile plaques and in the cerebrovasculature in Alzheimer's disease (AD), causes a dramatic immune response that prevents plaque formation and clears accumulated Aβ in transgenic mice. In a clinical trial of Aβ immunization, some patients developed meningoencephalitis and hemorrhages. Neuropathological investigations of patients who died after the trial showed clearance of amyloid pathology, but also a powerful immune response involving activated T cells probably underlying the negative effects of the immunization.
To define the impact of T cells on this inflammatory response we used passive immunization and adoptive transfer to separate the effect of IgG and T cell mediated effects on microhemorrhage in APPPS1 transgenic mice. Neither anti Aβ IgG nor adoptively transferred T cells, alone, led to increased cerebrovascular damage. However, the combination of adoptively transferred T cells and passive immunization led to massive cerebrovascular bleeding that ranged from multiple microhemorrhages in the parenchyma to large hematomas.
Our results indicate that vaccination can lead to Aβ and T cell induced cerebral micro-hemorrhages and acute hematomas, which are greatly exacerbated by T cell mediated activity.
PMCID: PMC3068114  PMID: 21388539
3.  Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain 
Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P < .05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis.
PMCID: PMC3014771  PMID: 21234373
4.  A reporter of local dendritic translocation shows plaque related loss of neural system function in APP transgenic mice 
Although neuronal communication is thought to be summated within local dendritic segments, no technique is currently available to monitor activity in vivo at this level of resolution. To overcome this challenge, we developed an optical reporter of neuronal activity utilizing the coding sequence of Venus, flanked by short stretches of the 5' and 3' untranslated regions from CAMKIIα. This reporter takes advantage of the fact that CAMKIIα mRNA is transported to the dendrite and locally translated in an activity dependent manner (Aakalu et al., 2001). Using adeno associated virus (AAV), we used this reporter to study neuronal activity in adult mice. Exposure of the mice to an enriched environment led to enhancement of Venus expression in dendritic segments of somatosensory cortex, demonstrating in vivo that dendritic mRNA translocation and local transcription occur in response to physiologically relevant stimuli. We then utilized this system to examine the impact of Alzheimer related local amyloid-β deposits on neural system function, to test the hypothesis that plaques are toxic. In APPswe/PS1d9 (APP/PS1) mice, neurons close to plaques, and dendritic segments close to plaques, both showed diminished fluorescent intensity and therefore neuronal activity. In contrast to wildtype mice, fluorescent intensity in neurons near plaques in transgenic mice did not increase after environmental enrichment. These data indicate that neuronal activity in dendritic segments and neurons in the vicinity of a plaque is decreased compared to wildtype mice, supporting the idea that plaques are a focal lesion leading to impaired neural system function.
PMCID: PMC2789808  PMID: 19812338
Alzheimer’s disease; senile plaque; neuritic alterations; APP/PS1 transgenic mice; Adeno associated virus; calcium/calmodulin-dependent kinase II
5.  Passive immunotherapy rapidly increases structural plasticity in a mouse model of Alzheimer disease 
Neurobiology of disease  2008;33(2):213-220.
Senile plaque-associated changes in neuronal connectivity such as altered neurite trajectory, dystrophic swellings, and synapse and dendritic spine loss are thought to contribute to cognitive dysfunction in Alzheimer’s disease and mouse models. Immunotherapy to remove amyloid beta is a promising therapy that causes recovery of neurite trajectory and dystrophic neurites over a period of days. The acute effects of immunotherapy on neurite morphology at a time point when soluble amyloid has been cleared but dense plaques are not yet affected are unknown. To examine whether removal of soluble amyloid β (Aβ) has a therapeutic effect on dendritic spines, we explored spine dynamics within one hour of applying a neutralizing anti Aβ antibody. This acute treatment caused a small but significant increase in dendritic spine formation in PDAPP brain far from plaques, without affecting spine plasticity near plaques or average dendritic spine density. These data support the hypothesis that removing toxic soluble forms of amyloid-beta rapidly increases structural plasticity possibly allowing functional recovery of neural circuits.
PMCID: PMC2672591  PMID: 19028582
Alzheimer; dendritic spine; immunotherapy; mouse model; structural plasticity

Results 1-5 (5)