Neuropsychiatric Disturbances in Alzheimer’s Disease: What have We Learned from Neuropathological Studies?

Author(s):

Debby Van Dam, Yannick Vermeiren, Alain D. Dekker, Petrus J.W. Naudé and Peter P. De DeynPages 1-20 (20)

Abstract:

Neuropsychiatric symptoms (NPS) are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. The near universal prevalence of NPS in Alzheimer’s disease (AD), combined with their disabling effects on patients and caregivers, is contrasted by the fact that few effective and safe treatments exist, which is in part to be attributed to our incomplete understanding of the neurobiology of NPS. In this review, we describe the pathological alterations typical for AD, including spreading and evolution of burden, effect on the molecular and cellular integrity, functional consequences and atrophy of NPS-relevant brain regions and circuits in correlation with specific NPS assessments. It is thereby clearly established that NPS are fundamental expressions of the underlying neurodegenerative brain disease and not simply reflect the patients’ secondary response to their illness. Neuropathological studies, moreover, include a majority of end-stage patient samples, which may not correctly represent the pathophysiological environment responsible for particular NPS that may already be present in an early stage, or even prior to AD diagnosis. The burdensome nature and high prevalence of NPS, in combination with the absence of effective and safe pharmacotherapies, provide a strong incentive to continue neuropathological and neurochemical, as well as imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.

Keywords:

Aggression, amyloid, depression, neurofibrillary tangles, neuronal loss, psychosis, neurotransmitter

Affiliation:

Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium

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Decreased Myelinated Fibers in the Hippocampal Dentate Gyrus of the Tg2576 Mouse Model of Alzheimer’s Disease

Author(s):

Wei Lu, Shu Yang, Lei Zhang, Lin Chen, Feng-lei Chao, Yan-min Luo, Qian Xiao, Heng-wei Gu, Rong Jiang and Yong TangPages 1-8 (8)

Abstract:

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is characterized by deficits in cognition and memory. Although amyloid-β (Aβ) accumulation is known to be the earliest pathological event that triggers subsequent neurodegeneration, how Aβ accumulation causes behavioral deficits remains incompletely understood. In this study, using the Morris water maze test, ELISA and stereological methods, we examined spatial learning and memory performance, the soluble Aβ concentration and the myelination of fibers in the hippocampus of 4-, 6-, 8- and 10-month-old Tg2576 AD model mice. Our results showed that spatial learning and memory performance was significantly impaired in the Tg2576 mice compared to the WT controls and that the myelinated fiber length in the hippocampal dentate gyrus (DG) was markedly decreased from 0.33 ± 0.03 km in the WT controls to 0.17 ± 0.02 km in the Tg2576 mice at 10 months of age. However, the concentrations of soluble Aβ40 and Aβ42 were significantly increased as early as 4-6 months of age. The decreased myelinated fiber length in the DG may contribute to the spatial learning and memory deficits of Tg2576 mice. Therefore, we suggest that the significant accumulation of soluble Aβ may serve as a preclinical biomarker for AD diagnosis and that protecting myelinated fibers may represent a novel strategy for delaying the progression of early-stage AD.

Affiliation:

Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, PR China

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Defining the earliest pathological changes of Alzheimer’s disease

Author(s):

James C. Vickers, Stan Mitew, Adele Woodhouse, Carmen M. Fernandez-Martos, Mathew T. Kirkcaldie, Alison J. Canty, Graeme H. McCormack and Anna E. KingPages 281-287 (7)

Abstract:

The prospects for effectively treating well-established dementia, such as Alzheimer’s disease (AD), are slim, due to the destruction of key brain pathways that underlie higher cognitive function. There has been a substantial shift in the field towards detecting conditions such as AD in their earliest stages, which would allow preventative or therapeutic approaches to substantially reduce risk and/or slow the progression of disease. AD is characterized by hallmark pathological changes such as extracellular Aβ plaques and intracellular neurofibrillary pathology, which selectively affect specific subclasses of neurons and brain circuits. Current evidence indicates that Aβ plaques begin to form many years before overt dementia, a gradual and progressive pathology which offers a potential target for early intervention. Early Aβ changes in the brain result in localized damage to dendrites, axonal processes and synapses, to which excitatory synapses and the processes of projection neurons are highly vulnerable. Aβ pathology is replicated in a range of transgenic models overexpressing mutant human familial AD genes (eg APP and presenilin 1). Studying the development of aberrant regenerative and degenerative changes in neuritic processes associated with Aβ plaques may represent the best opportunity to understand the relationship between the pathological hallmarks of AD and neuronal damage, and to develop early interventions to prevent, slow down or mitigate against Aβ pathology and/or the neuronal alterations that leads to cognitive impairment.

Keywords:

Alzheimer’s disease, amyloid precursor protein, Aß, plaque, dystrophic neurite, selective vulnerability, transgenic mice.

Affiliation:

Wicking Dementia Research and Education Centre, Faculty of Health, University of Tasmania, Hobart, Tasmania 7000, Australia.

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Perspectives on the Tertiary Prevention Strategy for Alzheimer’s Disease

Author(s):

Xian-Le Bu, Shu-Sheng Jiao, Yan Lian and Yan-Jiang WangPages 307-316 (10)

Abstract:

Amyloid-beta (Aβ) plays a pivotal role in Alzheimer’s disease (AD) pathogenesis, and is the most promising disease-modifying target for AD. A succession of failures in Aβ-targeting clinical trials, however, has prompted questions on whether Aβ is the true cause of AD and a valid therapeutic target. Therefore, current therapeutic targets and intervention strategies must be reconsidered. In addition to Aβ, multiple pathological events such as tau hyperphosphorylation, oxidative stress and neuroinflammation are involved in the disease pathogenesis and cause cross-talk between these pathological pathways, which synergistically drive disease progression. Increasing evidence also reveals that the pathogenesis varies at different stages of the disease. Therefore, targeting Aβ alone at all stages of the disease would not be sufficient to halt or reverse disease progression. In the light of the pathophysiologic similarities between the development of ischemic stroke and AD, we can formulate management strategies for AD from the successful practice of ischemic stroke management, namely the tertiary prevention strategy. These new perspectives of tertiary prevention target both Aβ and different pathological pathways of AD pathogenesis at different stages of the disease, and may represent a promising avenue for the effective prevention and treatment of AD.

Keywords:

Alzheimer's disease, beta-amyloid, tau hyperphosphorylation, stroke, therapeutic strategy.

Affiliation:

Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.

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Oral Triphenylmethane Food Dye Analog, Brilliant Blue G, Prevents Neuronal Loss in APPSwDI/NOS2-/- Mouse Model

Author(s):

Jacob A. Irwin, Alev Erisir and Inchan KwonPages 663-677 (15)

Abstract:

Reducing amyloid-β (Aβ) accumulation is a promising strategy for developing Alzheimer’s Disease (AD) therapeutics. We recently reported that a triphenylmethane food dye analog, Brilliant Blue G (BBG), is a dose-dependent modulator of in vitro amyloid-β aggregation and cytotoxicity in cell-based assays. Following up on this recent work, we sought to further evaluate this novel modulator in a therapeutically-relevant AD transgenic mouse model. BBG was orally administered to APPSwDI/NOS2-/- mice for three months in order to assess its biocompatibility, its permeability across the blood-brain barrier, and its efficacy at rescuing AD pathology. The results showed that BBG was well-tolerated, caused no significant weight change/unusual behavior, and was able to significantly cross the AD blood-brain barrier in APPSwDI/NOS2-/- mice. Immunohistochemical and electron microscopic analysis of the brain sections revealed that BBG was able to significantly prevent neuronal loss and reduce intracellular APP/Aβ in hippocampal neurons. This is the first report of 1) the effect of Brilliant Blue G on neuronal loss in a transgenic animal model of AD, 2) oral administration of BBG to affect a protein conformation/aggregation disease, and 3) electron microscopic ultrastructural analysis of AD pathology in APPSwDI/NOS2-/- mice.

Keywords:

Alzheimer’s Disease, amyloid-β, blood-brain barrier, intracellular amyloid-β, neuronal loss, triphenylmethane dye.

Affiliation:

102 Gilmer Hall, PO Box 400400, Department of Psychology, University of Virginia, Charlottesville, Virginia 22904, USA., School of Materials Science and Engineering, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 61005, Republic of Korea.

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