Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of beta-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between beta-amyloid and tau alterations may take place in vivo

Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly: POEM: Odor Memory Biomarker in Normal Elderly

To relate a novel test of identifying and recalling odor percepts to biomarkers of Alzheimer’s Disease (AD) in well-characterized elderly individuals, ranging from cognitively normal to demented

The influence of semantic and phonological factors on syntactic decisions: An event-related brain potential study

During language production and comprehension, information about a word's syntactic properties is sometimes needed. While the decision about the grammatical gender of a word requires access to syntactic knowledge, it has also been hypothesized that semantic (i.e., biological gender) or phonological information (i.e., sound regularities) may influence this decision. Event-related potentials (ERPs) were measured while native speakers of German processed written words that were or were not semantically and/or phonologically marked for gender. Behavioral and ERP results showed that participants were faster in making a gender decision when words were semantically and/or phonologically gender marked than when this was not the case, although the phonological effects were less clear. In conclusion, our data provide evidence that even though participants performed a grammatical gender decision, this task can be influenced by semantic and phonological factors

Endocytic Pathway Abnormalities Precede Amyloid β Deposition in Sporadic Alzheimer’s Disease and Down Syndrome : Differential Effects of APOE Genotype and Presenilin Mutations

Endocytosis is critical to the function and fate of molecules important to Alzheimer’s disease (AD) etiology, including the β protein precursor (βPP), amyloid β (Aβ) peptide, and apolipoprotein E (ApoE). Early endosomes, a major site of Aβ peptide generation, are markedly enlarged within neurons in the Alzheimer brain, suggesting altered endocytic pathway (EP) activity. Here, we show that neuronal EP activation is a specific and very early response in AD. To evaluate endocytic activation, we used markers of internalization (rab5, rabaptin 5) and recycling (rab4), and found that enlargement of rab5-positive early endosomes in the AD brain was associated with elevated levels of rab4 immunoreactive protein and translocation of rabaptin 5 to endosomes, implying that both endocytic uptake and recycling are activated. These abnormalities were evident in pyramidal neurons of the neocortex at preclinical stages of disease when Alzheimer-like neuropathology, such as Aβ deposition, was restricted to the entorhinal region. In Down syndrome, early endosomes were significantly enlarged in some pyramidal neurons as early as 28 weeks of gestation, decades before classical AD neuropathology develops. Markers of EP activity were only minimally influenced by normal aging and other neurodegenerative diseases studied. Inheritance of the ε4 allele of APOE, however, accentuated early endosome enlargement at preclinical stages of AD. By contrast, endosomes were normal in size at advanced stages of familial AD caused by mutations of presenilin 1 or 2, indicating that altered endocytosis is not a consequence of Aβ deposition. These results identify EP activation as the earliest known intraneuronal change to occur in sporadic AD, the most common form of AD. Given the important role of the EP in Aβ peptide generation and ApoE function, early endosomal abnormalities provide a mechanistic link between EP alterations, genetic susceptibility factors, and Aβ generation and suggest differences that may be involved in Aβ generation and β amyloidogenesis in subtypes of AD

Statistical physics and Alzheimer's disease

Abstract We discuss the possible utility of statistical physics in elucidating some of the puzzling phenomena that seem to occur in the brains of patients a ected with Alzheimer's disease. Further, we report three speciÿc results from this approach: (i) The size distribution of senile plaques appears to be log-normal, (ii) We develop a model for growth of senile plaques that is characterized by both aggregation and disaggregation, and (iii) We quantify neuron architecture and ÿnd quantitative evidence for the existence of microcolumns positioned at right angles to the known lamina

Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue

Abstract [F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick’s disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. We also directly compared the binding properties of [F-18]-MK-6240 and [F-18]-AV-1451 in human tissue, and examined potential nonspecific binding of both tau tracers to monoamine oxidases (MAO) by using autoradiography in the presence of selective monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors. Our data indicate that MK-6240 strongly binds to neurofibrillary tangles in Alzheimer disease but does not seem to bind to a significant extent to tau aggregates in non-Alzheimer tauopathies, suggesting that it may have a limited utility for the in vivo detection of these pathologies. There is no evidence of binding to lesions containing β-amyloid, α-synuclein or TDP-43. In addition, we identified MK-6240 strong off-target binding to neuromelanin and melanin-containing cells, and some weaker binding to areas of hemorrhage. These binding patterns are nearly identical to those previously reported by our group and others for [F-18]-AV-1451. Of note, [F-18]-MK-6240 and [F-18]-AV-1451 autoradiographic binding signals were only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline, suggesting that MAO enzymes do not appear to be a significant binding target of any of these two tracers. Together these novel findings provide relevant insights for the correct interpretation of in vivo [F-18]-MK-6240 PET imaging

Calpain-Cleavage of α-Synuclein : Connecting Proteolytic Processing to Disease-Linked Aggregation

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are both characterized pathologically by the presence of neuronal inclusions termed Lewy bodies (LBs). A common feature found in LBs are aggregates of α-synuclein (α-Syn), and although it is now recognized that α-Syn is the major building block for these toxic filaments, the mechanism of how this occurs remains unknown. In the present study, we demonstrate that proteolytic processing of α-Syn by the protease calpain I leads to the formation of aggregated high-molecular weight species and adoption of a β-sheet structure. To determine whether calpain-cleavage of α-Syn occurs in PD and DLB, we designed site-directed calpain-cleavage antibodies to α-Syn and tested their utility in several animal model systems. Detection of calpain-cleaved α-Syn was evident in mouse models of cerebral ischemia and PD and in a Drosophila model of PD. In the human PD and DLB brain, calpain-cleaved α-Syn antibodies immunolabeled LBs and neurites in the substantia nigra. Moreover, calpain-cleaved α-Syn fragments identified within LBs colocalized with activated calpain in neurons of the PD and DLB brains. These findings suggest that calpain I may participate in the disease-linked aggregation of α-Syn in various α-synucleinopathies

Tau - amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid induced disruption of axonal projections and exacerbated axonal pathology

Early observations of the patterns of neurofibrillary tangles and amyloid plaques in Alzheimer’s disease suggested a hierarchical vulnerability of neurons for tangles, and a widespread nonspecific pattern of plaques that nonetheless seemed to correlate with the terminal zone of tangle bearing neurons in some instances. The first neurofibrillary cortical lesions in Alzheimer’s disease occur in the entorhinal cortex, thereby disrupting the origin of the perforant pathway projection to the hippocampus, and amyloid deposits are often found in the molecular layer of the dentate gyrus, which is the terminal zone of the entorhinal cortex. We have modeled these anatomical changes in a transgenic mouse model that overexpresses both P301L tau (uniquely in the medial entorhinal cortex), and mutant APP/PS1 (in a widespread distribution), to examine the anatomical consequences of early tangles, plaques, or the combination. We find that tau uniformly occupies the terminal zone of the perforant pathway in tau expressing mice. By contrast, the addition of amyloid deposits in this area leads to disruption of the perforant pathway terminal zone and apparent aberrant distribution of tau containing axons. Moreover, human P301L tau containing axons appear to increase the extent of dystrophic axons around plaques. Thus the presence of amyloid deposits in the axonal terminal zone of pathological tau containing neurons profoundly impacts their normal connectivity

Increased sensitivity to MPTP in human alpha-synuclein A30P transgenic mice

In addition to genetic factors, environmental factors have long been suspected to contribute to the pathogenesis of Parkinson's disease (PD). We investigated the possible interaction between genetic factors and neurotoxins by testing whether alpha-synuclein A30P Tg5093 transgenic mice show increased sensitivity to secondary toxic insults like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone. While sensitivity to chronic treatment with rotenone was not enhanced in the Tg5093 line, chronic treatment with 80 or 150 mg/kg MPTP resulted in increased deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) positive neurons and striatal dopamine (DA) levels in Tg5093 mice when compared to non-transgenic littermate controls. Thus, the results of this study demonstrate a role for the overexpression of mutant human alpha-synuclein A30P in increased vulnerability of DA neurons to MPTP