Understanding the neural mechanisms underlying brain dysfunction induced by amyloid beta-protein (A&#x3b2;) represents one of the major challenges for Alzheimer&#x2019;s disease (AD) research. The most evident symptom of AD is a severe decline in cognition. Cognitive processes, as any other brain function, arise from the activity of specific cell assemblies of interconnected neurons that generate neural network dynamics based on their intrinsic and synaptic properties. Thus, the origin of A&#x3b2;-induced cognitive dysfunction, and possibly AD-related cognitive decline, must be found in specific alterations in properties of these cells and their consequences in neural network dynamics. The well-known relationship between AD and alterations in the activity of several neural networks is reflected in the slowing of the electroencephalographic (EEG) activity. Some features of the EEG slowing observed in AD, such as the diminished generation of different network oscillations, can be induced in vivo and in vitro upon A&#x3b2; application or by A&#x3b2; overproduction in transgenic models. This experimental approach offers the possibility to study the mechanisms involved in cognitive dysfunction produced by A&#x3b2;. This type of research may yield not only basic knowledge of neural network dysfunction associated with AD, but also novel options to treat this modern epidemic.

Fernando Pe&#xf1;a-Ortega

Amyloid Beta-Protein and Neural Network Dysfunction

Atherosclerosis and apolipoprotein E &#x3b5;4 (APOE4) genotype are risk factors for Alzheimer&#x2019;s disease (AD) and cardiovascular disease (CVD). Sex differences exist in prevalence and manifestation of both diseases. We investigated sex differences respective to aging, focusing on cognitive parameters in apoE4 and apoE knockout (ko) mouse models of AD and CVD. Presynaptic density and neurogenesis were investigated immunohistochemically in male and female apoE4, apoE ko, and wild-type mice. Middle-aged female apoE4 mice showed decreased presynaptic density in the inner molecular layer of the dentate gyrus of the hippocampus. Middle-aged female apoE ko mice showed a trend towards increased neurogenesis in the hippocampus compared with wild-type mice. No differences in these parameters could be observed in middle-aged male mice. Specific harmful interactions between apoE4 and estrogen could be responsible for decreased presynaptic density in female apoE4 mice. The trend of increased neurogenesis found in female apoE ko mice supports previous studies suggesting that temporarily increased amount of synaptic contacts and/or neurogenesis is a compensatory mechanism for synaptic failure. To our knowledge, no other studies investigating presynaptic density in aging female apoE4 or apoE ko mice are available. Sex-specific differences between APOE genotypes could account for some sex differences in AD and CVD.

A. Rijpma

D. Jansen

I. A. C. Arnoldussen

X. T. Fang

M. Wiesmann

M. P. C. Mutsaers

P. J. Dederen

C. I. F. Janssen

A. J. Kiliaan

Sex Differences in Presynaptic Density and Neurogenesis in Middle-Aged ApoE4 and ApoE Knockout Mice

Neurodegenerative diseases are multifactorial debilitating disorders of the nervous system that affect approximately 30 millionindividuals worldwide. Neurodegenerative diseases such as Alzheimer&#x2019;s, Parkinson&#x2019;s, Huntington&#x2019;s, and amyotrophic lateral sclerosis diseases are the consequence of misfolding and dysfunctional trafficking of proteins. Beside that, mitochondrial dysfunction, oxidative stress, and/or environmental factors strongly associated with age have also been implicated in causing neurodegeneration. After years of intensive research, considerable evidence has accumulated that demonstrates an important role of these factors in the etiology of common neurodegenerative diseases. Despite the extensive efforts that have attempted to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. However, in order to explore the therapeutic interventions directed towards treatment of neurodegenerative diseases, neuroscientists are now fully exploiting the data obtained from studies of these basic mechanisms that have gone awry. The novelty of these mechanisms represents a challenge to the identification of viable drug targets and biomarkers for early diagnosis of the diseases. In this paper, we are reviewing various aspects associated with the disease and the recent trends that may have an application for the treatment of the neurodegenerative disorders.

Saba Sheikh

Safia

Ejazul Haque

Snober S. Mir

Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of disorders affecting both motor and sensory neurons in the peripheral nervous system. Mutations in the MFN2 gene cause an axonal form of CMT, CMT2A. The V705I variant in MFN2 has been previously reported as a disease-causing mutation in families with CMT2. We identified an affected index patient from an Australian multigenerational family with the V705I variant. Segregation analysis showed that the V705I variant did not segregate with the disease phenotype and was present in control individuals with an allele frequency of 4.4&#x25;. We, therefore, propose that the V705I variant is a polymorphism and not a disease-causing mutation as previously reported.

Obaid M. Albulym

Danqing Zhu

Stephen Reddel

Marina Kennerson

Garth Nicholson

The MFN2 V705I Variant Is Not a Disease-Causing Mutation: A Segregation Analysis in a CMT2 Family

We present results of a study investigating evaluative learning in dementia patients with a classic evaluative conditioning paradigm. Picture pairs of three unfamiliar faces with liked, disliked, or neutral faces, that were rated prior to the presentation, were presented 10 times each to a group of dementia patients (N = 15) and healthy controls (N = 14) in random order. Valence ratings of all faces were assessed before and after presentation. In contrast to controls, dementia patients changed their valence ratings of unfamiliar faces according to their pairing with either a liked or disliked face, although they were not able to explicitly assign the picture pairs after the presentation. Our finding suggests preserved evaluative conditioning in dementia patients. However, the result has to be considered preliminary, as it is unclear which factors prevented the predicted rating changes in the expected direction in the control group.

Andreas Blessing

Jacqueline Z&#xf6;llig

Roland Weierstall

Gerhard Dammann

Mike Martin

Evaluative Conditioning with Facial Stimuli in Dementia Patients

Dementia is a complex disorder that mostly affects the elderly and represents a significant and growing public health burden in the world. Alzheimer&#x2019;s disease (AD)- associated dementia and dementia with Lewy bodies (DLB) are the most common forms of dementia, in which oxidative stress is significantly involved. Oxidative stress mechanisms may have clinical applications, that is, providing information for potential biomarkers. Thus brain-rich peptides with an antioxidant property, such as CART (cocaine- and amphetamine-regulated transcript), may be promising new markers.  This paper summarizes the progress in research regarding oxidative stress in dementia with a focus on potential biomarkers in the cerebrospinal fluid (CSF) in the main forms of dementia. Other central and peripheral biomarkers, especially those considered oxidative stress related, are also discussed. This paper aims to provide information to improve current understanding of the pathogenesis and progression of dementia. It also offers insight into the differential diagnosis of AD and DLB.

Peizhong Mao

Oxidative Stress and Its Clinical Applications in Dementia

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Journal of Neurodegenerative Diseases