Journal of Alzheimer's Disease - Volume 33, issue s1

Authors: Puzzo, Daniela | Arancio, Ottavio

Article Type: Review Article

Abstract: Amyloid-β peptide (Aβ) is considered a key protein in the pathogenesis of Alzheimer's disease (AD) because of its neurotoxicity and capacity to form characteristic insoluble deposits known as senile plaques. Aβ derives from amyloid-β protein precursor (AβPP), whose proteolytic processing generates several fragments including Aβ peptides of various lengths. The normal function of AβPP and its fragments remains poorly understood. While some fragments have been suggested to have a function in normal physiological cellular processes, Aβ has been widely considered as a “garbage” fragment that becomes toxic when it accumulates in the brain, resulting in impaired synaptic function and memory. …Aβ is produced and released physiologically in the healthy brain during neuronal activity. In the last 10 years, we have been investigating whether Aβ plays a physiological role in the brain. We first demonstrated that picomolar concentrations of a human Aβ42 preparation enhanced synaptic plasticity and memory in mice. Next, we investigated the role of endogenous Aβ in healthy murine brains and found that treatment with a specific antirodent Aβ antibody and an siRNA against murine AβPP impaired synaptic plasticity and memory. The concurrent addition of human Aβ42 rescued these deficits, suggesting that in the healthy brain, physiological Aβ concentrations are necessary for normal synaptic plasticity and memory to occur. Furthermore, the effect of both exogenous and endogenous Aβ was seen to be mediated by modulation of neurotransmitter release and α7-nicotinic receptors. These findings need to be taken into consideration when designing novel therapeutic strategies for AD. Show more

Keywords: Amyloid-β peptide, hippocampus, memory, nicotinic receptor, synaptic plasticity

DOI: 10.3233/JAD-2012-129033

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S111-S120, 2013

Authors: Wang, Jian-Zhi | Xia, Yi-Yuan | Grundke-Iqbal, Inge | Iqbal, Khalid

Article Type: Review Article

Abstract: Microtubule associated protein tau is a phosphoprotein which potentially has 80 serine/threonine and 5 tyrosine phosphorylation sites. Normal brain tau contains 2-3 moles of phosphate per mole of the protein. In Alzheimer's disease brain, tau is abnormally hyperphosphorylated to a stoichiometry of at least three-fold greater than normal tau, and in this altered state it is aggregated into paired helical filaments forming neurofibrillary tangles, a histopathological hallmark of the disease. The abnormal hyperphosphorylation of tau is also a hallmark of several other related neurodegenerative disorders, called tauopathies. The density of neurofibrillary tangles in the neocortex correlates with dementia and, hence, …is a rational therapeutic target and an area of increasing research interest. Development of rational tau-based therapeutic drugs requires understanding of the role of various phosphorylation sites, protein kinases and phosphatases, and post-translational modifications that regulate the phosphorylation of this protein at various sites, as well as the molecular mechanism by which the abnormally hyperphosphorylated tau leads to neurodegeneration and dementia. In this article we briefly review the progress made in these areas of research. Show more

Keywords: Alzheimer's disease, neurofibrillary degeneration, post-translational modifications of tau, protein kinases, protein phosphatases, tau phosphorylation

DOI: 10.3233/JAD-2012-129031

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S123-S139, 2013

Authors: Hernandez, Felix | Lucas, Jose J. | Avila, Jesus

Article Type: Review Article

Abstract: Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that plays a key role in the pathogenesis of Alzheimer's disease (AD). GSK3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired helical filaments, and GSK3 activity contributes both to amyloid-β production and amyloid-β-mediated neuronal death. Thus, mice generated in our laboratory with conditional overexpression of GSK3 in forebrain neurons (Tet/GSK3β mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis, as well as spatial learning deficit. In this review, we describe recent contributions of our group showing that transgene shutdown …in that animal model leads to normal GSK3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK3 inhibitors for AD therapeutics. In addition, we have combined transgenic mice overexpressing the enzyme GSK3β with transgenic mice expressing tau with a triple FTDP-17 mutation that develop prefibrillar tau-aggregates. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Further, it is possible to partially reverse tau pathology in advanced stages of the disease, although the presence of already assembled neurofibrillary tangle-like structures cannot be reversed. Show more

Keywords: Alzheimer's disease, GSK3, tau

DOI: 10.3233/JAD-2012-129025

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S141-S144, 2013

Authors: Cook, Casey | Petrucelli, Leonard

Article Type: Review Article

Abstract: The pathological accumulation of the microtubule-binding protein tau is linked to an increasing number of neurodegenerative conditions associated with aging, though the mechanisms by which tau accumulates in disease are unclear. In this review, we will summarize our previous research assessing the mechanism of action, as well as the therapeutic potential of Hsp90 inhibition for the treatment of tauopathies. Specifically, we describe the development of a high-throughput screening approach to identify and rank compounds, and demonstrate the selective elimination of aberrant p-tau species in the brain following treatment with an Hsp90 inhibitor. Additionally, we identify CHIP as an essential component …of the Hsp90 chaperone complex that mediates tau degradation, and present evidence to suggest that CHIP functions to identify and sequester neurotoxic tau species. Finally, we discuss recent data identifying an additional mechanism by which CHIP modulates protein triage decisions involving Hsp90. Specifically, CHIP indirectly regulates Hsp90 chaperone activity by modulating steady-state levels of the Hsp90 deacetylase, HDAC6, thus influencing both the acetylation state and function of Hsp90. Thus future research directions will focus on the manipulation of this network to promote degradation of pathogenic tau species in disease. Show more

Keywords: Alzheimer's disease, chaperone, CHIP, Hsp70, Hsp90, tau

DOI: 10.3233/JAD-2012-129008

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S145-S151, 2013

Authors: Braak, Heiko | Del Tredici, Kelly

Article Type: Review Article

Abstract: Tau lesions (pretangles, neuropil threads, neurofibrillary tangles) that develop in a few types of nerve cells in the brain are essential to the pathogenesis of Alzheimer's disease (AD). The formation of non-argyrophilic pretangles marks the beginning of the pathological process and is of increasing interest because it is temporally closer to the prevailing conditions that induce the pathological process underlying AD in contrast to late-stage disease. Not all of the pretangle material, however, converts into argyrophilic neurofibrillary lesions. The propensity to develop tau lesions may be related to the exceptionally protracted myelination of late developing portions in the human brain.

Keywords: Alzheimer's disease, AT8 immunocytochemistry, cytoskeleton, dementia, evolutionary medicine, Gallyas silver method, neurofibrillary tangles, pretangles, tau protein, tauopathies

DOI: 10.3233/JAD-2012-129029

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S155-S161, 2013

Authors: Matthews, Paul M. | Filippini, Nicola | Douaud, Gwenaëlle

Article Type: Review Article

Abstract: In our contribution to this special issue focusing on advances in Alzheimer's disease (AD) research since the centennial, we will briefly review some of our own studies applying magnetic resonance imaging (MRI) measures of function and connectivity for characterization of genetic contributions to the neuropathology of AD and as candidate biomarkers. We review how functional MRI during both memory encoding and at rest is able to define APOE4 genotype-dependent physiological changes decades before potential development of AD and demonstrate changes distinct from those with healthy aging. More generally, imaging provides a powerful quantitative measure of phenotype for understanding associations arising …from whole genome studies in AD. Structural connectivity measures derived from diffusion tensor MRI (DTI) methods offer additional markers of neuropathology arising from the secondary changes in axonal caliber and myelination that accompany decreased neuronal activity and neurodegeneration. We illustrate applications of DTI for more finely mapping neurodegenerative changes with AD in the thalamus in vivo and for defining neuropathological changes in the white matter itself. The latter efforts have highlighted how sensitivity to the neuropathology can be enhanced by using more specific DTI measures and interpreting them relative to knowledge of local white matter anatomy in the healthy brain. Together, our studies and related work are helping to establish the exciting potential of a new range of MRI methods as neuropathological measures and as biomarkers of disease progression. Show more

Keywords: Alzheimer's disease, biomarker, diffusion tensor imaging (DTI), fMRI, MRI

DOI: 10.3233/JAD-2012-129012

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S163-S172, 2013

Authors: Alafuzoff, Irina

Article Type: Review Article

Abstract: The invitation to contribute to “Alzheimer's Disease: Advances for a New Century” gave me an opportunity to briefly summarize my personal opinions about how the field of neuropathology has evolved. The goal is to briefly exemplify the changes that have influenced the way we conduct our diagnostic work as well as the way we interpret our results. From an era of histological stains, we have moved to visualization of altered proteins in predicted brain regions; we have also realized that in many aged subjects, not one but a plethora of co-pathologies are seen, and finally, we have become aware that …the degenerative process is initiated much earlier than we ever suspected. Show more

Keywords: Aging, Alzheimer's disease-related pathology, amyloid-β, co-morbidity, hyperphosphorylated tau, immunohistochemistry, neuropathology, α-synuclein

DOI: 10.3233/JAD-2012-129024

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S173-S179, 2013

Authors: Montine, Kathleen S. | Montine, Thomas J.

Article Type: Review Article

Abstract: Progressive cognitive impairment and its clinical culmination in dementia loom as a major public health problem in the coming generation of older adults, and this fact compels investigation to develop interventions that prevent, delay, or cure. The tools of anatomic pathology have provided key insights into the complex convergence of multiple diseases that commonly contribute to the dementia syndrome and its prodrome in the community setting, and they have suggested some exposures that may modulate disease burden. The tools of clinical pathology, in combination with neuroimaging, have revolutionized the approach to clinical investigation of Alzheimer's disease and are now doing …the same with Lewy body disease and vascular brain injury. The tools of anatomic and clinical pathology will continue to contribute to our understanding of these diseases as we advance toward effective interventions for the diseases that commonly cause cognitive impairment and dementia in older adults. Show more

Keywords: Alzheimer's disease, dementia, Lewy body disease, vascular brain injury

DOI: 10.3233/JAD-2012-129032

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S181-S184, 2013

Authors: Ubhi, Kiren | Masliah, Eliezer

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory deficits and other cognitive disturbances. Neuropathologically, AD is characterized by the progressive loss of basal forebrain cholinergic neurons that innervate the hippocampus and cortex and the abnormal extracellular accumulation of amyloid-β and intracellular tau protein. Current research on AD is focused on the mechanisms underlying the abnormal oligomerization, fibrillation, and accumulation of the amyloid-β and tau proteins, mechanisms that may alter the dynamics of this accumulation and on experimental therapeutics approaches aimed at the clearance of the abnormally folded proteins and other potentially neuroprotective interventions. This review will …summarize the main areas of investigation in AD and present ways forward for future work. Show more

Keywords: Autophagy, chaperone, dementia, immunotherapy, neurotrophic factors, transgenic

DOI: 10.3233/JAD-2012-129028

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S185-S194, 2013

Authors: Medeiros, Rodrigo | Chabrier, Meredith A. | LaFerla, Frank M.

Article Type: Review Article

Abstract: As the number of patients with Alzheimer's disease (AD) continues to rise, the need for efficacious therapeutics is becoming more and more urgent. Understanding the molecular relationship and interactions between Aβ and tau and their contribution to cognitive decline remain one of the most fundamental and unresolved questions in the AD field. Likewise, elucidating the initial triggers of disease pathology, as well as the impact of various factors such as stress and inflammation on disease progression, are equally important to fully understand this devastating disorder. Here we discuss recent studies that have illuminated the importance of key facilitators of disease …progression using the 3xTg-AD and CaM/Tet-DTA mouse models, and suggest viable targets for ameliorating both molecular pathology and cognitive decline. Show more

Keywords: 3xTg-AD, amyloid-β, animal model, inflammation, neuronal loss, tau, therapies

DOI: 10.3233/JAD-2012-129009

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S195-S210, 2013