Form Of Alzheimer Research Articles

Molecular Hydrogen Neuroprotection in Post-Ischemic Neurodegeneration in the Form of Alzheimer's Disease Proteinopathy: Underlying Mechanisms and Potential for Clinical Implementation-Fantasy or Reality?

Currently, there is a lot of public interest in naturally occurring substances with medicinal properties that are minimally toxic, readily available and have an impact on health. Over the past decade, molecular hydrogen has gained the attention of both preclinical and clinical researchers. The death of pyramidal neurons in especially the CA1 area of the hippocampus, increased permeability of the blood-brain barrier, neuroinflammation, amyloid accumulation, tau protein dysfunction, brain atrophy, cognitive deficits and dementia are considered an integral part of the phenomena occurring during brain neurodegeneration after ischemia. This review focuses on assessing the current state of knowledge about the neuroprotective effects of molecular hydrogen following ischemic brain injury. Recent studies in animal models of focal or global cerebral ischemia and cerebral ischemia in humans suggest that hydrogen has pleiotropic neuroprotective properties. One potential mechanism explaining some of the general health benefits of using hydrogen is that it may prevent aging-related changes in cellular proteins such as amyloid and tau protein. We also present evidence that, following ischemia, hydrogen improves cognitive and neurological deficits and prevents or delays the onset of neurodegenerative changes in the brain. The available evidence suggests that molecular hydrogen has neuroprotective properties and may be a new therapeutic agent in the treatment of neurodegenerative diseases such as neurodegeneration following cerebral ischemia with progressive dementia. We also present the experimental and clinical evidence for the efficacy and safety of hydrogen use after cerebral ischemia. The therapeutic benefits of gas therapy open up new promising directions in breaking the translational barrier in the treatment of ischemic stroke.

Effect of stimuli type on affective memory of patients with different severities of cognitive impairment

Objectives To understand the differences in affective memory performance under different degrees of cognitive impairment, this study recruited older people with different degrees of cognitive impairment, to perform emotion recognition memory tasks. Methods Fifty-four elderly participants aged (65-85 years) were recruited. Of these, 18 had mild cognitive impairment, 18 had a mild form of Alzheimer’s disease, and the remaining 18 were healthy. Factors such as the different emotional valences (positive, neutral, or negative) and stimulus types (pictures, words, or sounds) were manipulated to explore their influences on the emotion recognition memory of people with different degrees of cognitive impairment. Results The results showed that people’s performance to positive stimuli worsened as their degree of cognitive impairment increased. All participants had difficulty processing memory of affective sound stimuli compared to the other two stimulus types. Conclusions The results explain the decline in the cognitive ability process, in affective memory performance, of people with different degrees of cognitive impairment. This abnormal decline on affective memory performance could be an early diagnostic indicator of Alzheimer’s disease. The results can hopefully be used as a reference for subsequent research on cognition-related diseases and age-related decline, especially regarding affective memory.

Cross-Talk between Amyloid, Tau Protein and Free Radicals in Post-Ischemic Brain Neurodegeneration in the Form of Alzheimer's Disease Proteinopathy.

Recent years have seen remarkable progress in research into free radicals oxidative stress, particularly in the context of post-ischemic recirculation brain injury. Oxidative stress in post-ischemic tissues violates the integrity of the genome, causing DNA damage, death of neuronal, glial and vascular cells, and impaired neurological outcome after brain ischemia. Indeed, it is now known that DNA damage and repair play a key role in post-stroke white and gray matter remodeling, and restoring the integrity of the blood-brain barrier. This review will present one of the newly characterized mechanisms that emerged with genomic and proteomic development that led to brain ischemia to a new level of post-ischemic neuropathological mechanisms, such as the presence of amyloid plaques and the development of neurofibrillary tangles, which further exacerbate oxidative stress. Finally, we hypothesize that modified amyloid and the tau protein, along with the oxidative stress generated, are new key elements in the vicious circle important in the development of post-ischemic neurodegeneration in a type of Alzheimer’s disease proteinopathy.

A Semantic Agent-Based Safety Model for Alzheimer’sPatients for Driving

Alzheimer’s disease drastically affects the human neurological system, causing the death of neurons and synapses in cerebral cortex and other regions. Consequently, patients with Alzheimer’s disease require 24/7 care and assistance with daily life activities. This study uses an ontology-based semantic model to assist the Alzheimer’s patients through activity recognition in the focused scenario of driving. The safety model presented in this paper alerts the user if anything dangerous is about to happen when they enter a car or during driving. It should be noted that the model is specifically designed for the patients suffering from a mild form of Alzheimer’s disease. We have used semantics to define the objects and environment for the patients. After proper monitoring and evaluation, our model suggests a proper course of action based on semantic reasoning.

Association commits $14 million to novel drug trials in rare form of Alzheimer's.

Association commits $14 million to novel drug trials in rare form of Alzheimer's.

Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro

BackgroundAlzheimer’s disease (AD) is the most common form of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed to the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1, and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of a mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells (iPSCs).Methods iPSC lines from patients suffering from a familial form of Alzheimer’s disease and harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into brain microvascular endothelial cells (BMECs) following established differentiation protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporter activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1, and lysosomal acidification by acridine orange.ResultsiPSC-derived BMECs from the FAD patient presenting a mutation in the PSEN1 gene showed impaired barrier function compared to the FAD patient harboring a mutation in PSEN2 and to the control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2-BMECs displayed reduced bioenergetics, lysosomal acidification, autophagy, while showing an increase in radical oxygen species (ROS) production. Finally, PSEN1- and PSEN2-BMECs showed an elevated secretion of Aβ1–40 peptides compared to control-BMECs.ConclusionsOur study reports that iPSC-derived BMECs obtained from FAD patients showed impaired barrier properties and BMEC metabolism. In particular, mutation in the PSEN1 gene was associated with a more detrimental phenotype than mutation in PSEN2, as noted by a reduced barrier function, reduced drug efflux pump activity, and diminished glucose metabolism. Therefore, assessing the contribution of genetic mutations associated with Alzheimer’s disease will allow us to better understand the contribution of the BBB in dementia, but also other neurodegenerative diseases.

Blood amyloid-\u03b2 oligomerization associated with neurodegeneration of Alzheimer\u2019s disease

IntroductionOligomeric amyloid-ß is a major toxic species associated with Alzheimer’s disease pathogenesis. Methods used to measure oligomeric amyloid-β in the blood have increased in number in recent years. The Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) is a specific method to measure oligomerization tendencies in the blood. The objective of this study was to determine the association between amyloid-ß oligomerization in the plasma and structural changes of the brain.MethodsWe studied 162 subjects composed of 92 community-based normal healthy subjects, 17 with subjective cognitive decline, 14 with mild cognitive impairment and 39 with Alzheimer’s disease dementia. All subjects underwent MDS-OAβ and three-dimensional T1 magnetic resonance imaging. To determine the structural changes of the brain that are statistically correlated with MDS-OAβ level, we used voxel-based morphometry with corrections for age and total intracranial volume covariates.ResultsWe found brain volume reduction in the bilateral temporal, amygdala, parahippocampal and lower parietal lobe and left cingulate and precuneus regions (family-wise error, p < 0.05). Reduction was also found in white matter in proximity to the left temporal and bilateral lower parietal lobes and posterior corpus callosum (family-wise error, p < 0.05). Brain volume increment was not observed in any regions within grey or white matter.DiscussionFindings suggest that substantial correlation exists between amyloid ß oligomerization in the blood and brain volume reduction in the form of Alzheimer’s disease despite of uncertainty in the casual relationship.

Genetic Expression Profile of Cerebrovascular Endothelium During Development of Alzheimer's Disease

In 2018 alone, seven‐hundred thousand Americans of age 65 years and older will have a form of Alzheimer's disease (AD) by the end of their lives. Emerging evidence demonstrates the association of AD with impaired delivery of blood oxygen and nutrients to and throughout the brain. Cerebral arteries coordinate vasodilation through endothelium‐derived hyperpolarization (EDH); sequentially entailing stimulation of G protein‐coupled receptors (GPCRs), increases in intracellular Ca2+, activation of small‐ and intermediate‐conductance Ca2+‐activated K+ channels (SKCa/IKCa), and spread of negative intracellular charge (“hyperpolarization”) through cell‐to‐cell gap junctions. Thus, we tested the hypothesis that the genetic expression of EDH vasodilatory components may decline during progression of age‐related AD in mouse cerebrovascular endothelium. We used the triple mutation mouse model of AD (3xTgAD) to examine cerebrovascular genetic profiles for young control (YC; 1 to 2 mo), mild cognitive impairment (MCI; 4 to 5 mo), amyloid‐β plaques (Aβ; 6 to 8 mo), and plaques + neurofibrillary tangles (Aβ+Tau; ≥12 mo); 3 male and 3 female mice/group. Quantitative polymerase chain reaction (qPCR) and RNA sequencing were used to examine genetic expression of isolated cerebral artery endothelium and purified brain vessels respectively. The qPCR results demonstrate mixed expression of respective isoforms of purinergic receptors as indicated by no changes for P2ry1 (transcript for P2Y1) but ~35% and ~65% upregulation of P2ry2 (P2Y2) during Aβ and Aβ+Tau respectively. In contrast, the expression of ion channel mRNA in the form of major K+ channels (Kcnn3/Kcnn4, SKCa/IKCa &amp; Kcnj2, inward rectifying KIR2.1) and transient receptor potential channels (Trpv4, TRPV4) remains relatively stable throughout the life of the animal. Further, with the exception of Gja1 (Cx43), the expression of connexins composing gap junctions (Gja4, Cx37 &amp; Gja5, Cx40) increased by ≥ 20% during Aβ and Aβ+Tau. Finally, RNAseq data and pathway analysis demonstrate a &gt;two‐fold upregulation of genes integral to cardiovascular remodeling during Aβ+Tau vs. YC. Overall, these data indicate profound genetic alterations underlying cerebral blood vessel function corresponding to moment‐to‐moment regulation of blood flow and chronic maintenance of vascular structure. Pairing new found knowledge of vascular “signatures” with developmental phases of AD may offer unprecedented opportunities to maintain a healthy mind throughout the entirety of a standard lifespan (~80 to 100 years).Support or Funding InformationThis research is supported by Loma Linda University School of Medicine new faculty start‐up funds and National Institutes of Health grants R00AG047198 &amp; R56AG062169 (EJB).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Item distribution, internal consistency, and structural validity of the German version of the DEMQOL and DEMQOL\u2013proxy

BackgroundAccurate assessment of health-related quality of life as an endpoint in intervention studies is a major challenge in dementia research. The DEMQOL (29 items) and the proxy version (32 items), which is partly based on the DEMQOL, are internationally used instruments. To date, there is no information on the structural validity, item distribution, or internal consistency for the German language version of these questionnaires.MethodsThis psychometric study is based on a secondary data analysis of a sample of 201 outpatients with a mild form of Alzheimer’s disease (AD) and their informal caregivers. The informal caregivers who were interviewed were involved in the care of the person with AD several times per week. The analysis for the evaluation of the structural validity was performed using Mokken scale analysis. The internal consistency was calculated using the ρ of the Molenaar Sijtsma statistic and Cronbach’s α.ResultsFor both versions, four subscales were identified: [A] “positive emotions”, [B] “negative emotions”, [C] “physical and cognitive functioning”, and [D] “daily activities and social relationships”. For both instruments, the internal consistency of all subscales was considered “good” (ρ = 0.71–0.88, α = 0.72–0.87).ConclusionsThe results are a first indication of good construct validity of the instruments used for the German setting. We recommend further investigations of the test-retest reliability and the inter-rater reliability of the proxy instrument.

Exome sequencing in an Italian family with Alzheimer\u2019s disease points to a role for seizure-related gene 6 (SEZ6) rare variant R615H

BackgroundThe typical familial form of Alzheimer’s disease (FAD) accounts for about 5% of total Alzheimer’s disease (AD) cases. Presenilins (PSEN1 and PSEN2) and amyloid-β (A4) precursor protein (APP) genes carry all reported FAD-linked mutations. However, other genetic loci may be involved in AD. For instance, seizure-related gene 6 (SEZ6) has been reported in brain development and psychiatric disorders and is differentially expressed in the cerebrospinal fluid of AD cases.MethodsWe describe a targeted exome sequencing analysis of a large Italian kindred with AD, negative for PSEN and APP variants, that indicated the SEZ6 heterozygous mutation R615H is associated with the pathology.ResultsWe overexpressed R615H mutation in H4-SW cells, finding a reduction of amyloid peptide Aβ(1–42). Sez6 expression decreased with age in a mouse model of AD (3xTG-AD), but independently from transgene expression.ConclusionsThese results support a role of exome sequencing for disease-associated variant discovery and reinforce available data on SEZ6 in AD models.

"In the flesh": Narratives of family caregivers at risk of Early-onset Familial Alzheimer's Disease.

In the growing body of literature dealing with the consequences of family caregiving amongst people with dementia, there are few studies examining the impact of Early-onset Familial Alzheimer's Disease on caregivers. This study exposes the subjective experience of a group of family caregivers who themselves possess a genetic susceptibility to develop this form of dementia. We interviewed and analyzed the accounts of 27 caregivers belonging to family lineages carrying the E280A mutation for Early-onset Alzheimer's Disease. We utilized a phenomenological method to analyze these accounts, initially tracking seven theoretical categories (Anxiety, Depression, Burden, Resilience, Self-efficacy, Social Support, and Coping Strategies) and then subsequently two additional categories which emerged (Conceptions about the Disease and Other Vital Experiences Interfering with Caregiving). The results show that caring for a loved one while simultaneously running the risk of developing the same form of Alzheimer's Disease permeates the caregivers' experience both in a negative and a positive way. The continuous exposition to emotional stress in these caregivers should be seriously considered as they may be at risk of accelerating the onset of symptoms of Alzheimer's Disease, while simultaneously, early psychological symptoms of dementia may be masked by the emotional sequelae of caregiving, interfering with early diagnosis. Certainly, support services for the entire family group are suggested.

Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center

Given the importance of identifying prodromes of dementia with specific etiologies, we assessed whether seven latent classes of mild cognitive impairment (MCI), defined empirically based on cognitive, functional, and neuropsychiatric information at initial visit, are associated with distinct clinical outcomes and neuropathological features. We separated 6034 participants with a baseline diagnosis of MCI into seven latent classes using previously defined criteria. We found that these latent classes of MCI differed significantly in their clinical outcomes, survival time, and neuropathology. Two amnestic multi-domain subgroups, as well as two other subgroups with functional impairments and neuropsychiatric disturbances, were at higher risk of not only a ‘pure’ form of Alzheimer's disease (AD) pathology, but also a ‘mixed’ pathology consisting of both AD and vascular features. Moreover, the seven latent classes had different risks of Lewy bodies, hippocampal sclerosis, and frontotemporal lobar degeneration (FTLD). This study indicates that data-driven subgroups of MCI are clinicopathologically informative and, with refinement, could lead to targeted interventions focused on each etiology.

Mitochondrial distribution and trafficking in primary fibroblast derived from patients diagnosed with sporadic form of Alzheimer's and Parkinson's diseases

Mitochondrial distribution and trafficking in primary fibroblast derived from patients diagnosed with sporadic form of Alzheimer's and Parkinson's diseases

Effect of hypoxia on cholinesterase activity in rat sensorimotor cortex

This study reports the dynamics of changes in postnatal ontogenesis of the activity of soluble and membrane-bound forms of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in sensorimotor cortex of rats as well as the pattern of their changes after prenatal hypoxia (E14, 7% O2, 3 h) or acute hypoxia in adult animals (4 months, 7% O2, 3 h). In normally developing rats the activity of the membrane-bound AChE form in the sensorimotor cortex gradually increased up to the end of the first month after birth and remained at this high level during all further postnatal ontogenesis, while the activity of the soluble form of AChE reached its maximum on the 10th day after birth and decreased significantly by the end of the first month. In animals exposed to prenatal hypoxia the activity both of the soluble and membrane bound forms of AChE during the first two weeks after birth was 20-25% lower, as compared to controls but increased by the end of the first month and even exceeded the control values remaining increased up to old age (1.5 years). The activity of both BChE forms in rat sensorimotor cortex at all stages of postnatal ontogenesis was significantly lower than of AChE, although the dynamics of their changes was similar to that of AChE. Prenatal hypoxia led to a decrease in the activity of the membrane-bound form of BChE, as compared to controls, practically at all developmental stages studied, but was higher at the end of the first month after birth. At the same time, the activity of the soluble form of BChE was decreased only on the 20th day of development, as compared to the control, but increased from the end of the first month of life onwards. Acute hypoxia in adult rats also led to a decrease in the activity of both forms of AChE and BChE in the sensorimotor cortex but the dynamics of these changes was different for each enzyme. Thus, insufficient oxygen supply to the nervous tissue at different stages of ontogenesis has a significant effect on the activity and ratio of various forms of cholinesterases exhibiting either growth factor or signaling properties. This may lead to changes in brain development and formation of behavioural reactions, including learning and memory, and also increase the risk of development of the sporadic form of Alzheimer's disease (AD)--one of the most common neurodegenerative diseases of advanced age. This study expands our knowledge of the properties of brain cholinesterases under normal and pathological conditions and may be useful for developing new approaches towards prevention and treatment of AD.

A 58-year-old female with blurred vision and apraxia

A 58-year-old right handed woman, with 12 years of formal education, had a five-year history of slowly progressive blurred vision and apraxia. Five years before the examination she gradually became blurred vision and had difficulties identifying static objects within the visual field. Then she went to an ophthalmologist and received cataract surgery. However, the symptoms were not improved after surgery. Two years later, she had difficulty doing household chores and was unable to dress herself. She developed an anxiety disorder in the absence of prominent language or memory deficits. Five years after onset, she showed global cognitive decline and abilities of daily life decline. On neurological examination she was alert. Neuropsychological testing revealed a mini-mental state examination (MMSE) score of 20/30 with anomia, agraphia, alexia and partial impairment on time orientation. Biochemical investigations for disorders involving thyroid function, vitamin B 12 , and folate were unremarkable. A brain MRI showed diffuse cortical atrophy and hippocampus atrophy. An 18 F-FDG PET scan showed bilateral hypometabolism at the frontal lobes, tempoparietooccipital adjunction, posterior cingulate cortices and precuneus, insular lobes, caudate nuclei and right thalamus. An 11 C-PIB PET scan showed bilateral amyloid deposits at bilateral frontal lobes and occipital lobes, left temporal lobe and insular, basal ganglia, bilateral cingulate cortices and precuneus. No PSEN1, PSEN2 or APP mutations were identified. This early-onset patient had an unusual cognitive complaint, including visual agnosia and apraxia. The clinical features, structural and functional imaging findings of this case were compatible with the diagnosis of Posterior Cortical Atrophy (PCA). PCA is a neurodegenerative condition characterized by a progressive, often dramatic and relatively selective decline in visual processing skills and other functions subserved by parietal, occipital and occipito-temporal regions, relatively intact memory and language in the early stages, and atrophy of posterior brain regions. Often considered as an atypical or variant form of Alzheimer’s disease (AD), PCA typically presents in the mid-50s or early 60s with a variety of unusual symptoms, such as difficulty in interpreting, locating, or reaching for objects under visual guidance or difficulty in navigating. Understanding numbers and reading and writing or spelling may also be affected and, as the disease progresses, patients often develop a more diffuse pattern of cognitive dysfunction, ultimately leading to dementia. The vast majority (>80%) of PCA patients are found to have AD pathology as the cause of dementia at autopsy. Both PCA and AD patients show a similar pattern of high cortical binding on amyloid positron emission tomography (PET) imaging, and analogous changes in cerebrospinal fluid (CSF) level of Aβ42, total tau, and phosphorylated tau. PCA and AD show overlapping atrophy and hypometabolism/hypoperfusion in temporoparietal regions, suggesting a common anatomic focus of neurodegeneration. Structural neuroimaging with either MRI or CT initially shows greater atrophy of visual processing areas in parietotemporo-occipital cortex and relative sparing of critical memory regions in the medial temporal lobe. Over time, the neuroimaging profile of PCA may also merge with that of typical AD. This patient has five-year history of blurred vision and apraxia. At the time of examination, she has been in the stage of global cognitive declining. Diffuse cortical atrophy and hippocampus atrophy in MRI is very difficult to distinguish from typical AD. Hypometabolism and amyloid deposits from PET scan also showed overlapping with typical AD. doi: 10.3969/j.issn.1672-6731.2014.07.018

Immunization with a synthetic fragment 155–164 of neurotrophin receptor p75 prevents memory loss and decreases beta-amyloid level in mice with experimentally induced Alzheimer’s disease

Neurotoxic beta-amyloid peptide plays an important role in the pathology of Alzheimer's disease. In aggregated form it binds to several proteins on the surface of the brain cells leading to their death. p75 receptor in- volved in supporting of cell balance is one of the targets for toxic beta-amyloid. We proposed that induction of antibodies against potential binding sites of p75 with beta-amyloid can be a promising approach towards new drug development for Alzheimer's disease therapy. Four potentially immunoactive fragments of p75 were chosen and chemically synthesized. Investigation of immunoprotective effect of the peptide fragments carried out in mice with experimentally induced form of Alzheimer's disease helped to reveal two fragments effectively preserving murine memory from impairment. Results obtained by ELISA biochemical analysis showed that only immunization with fragment p75 155-164 led to significant decrease in beta-amyloid level in the brain of the experimental mice. Thus, immunization with both fragments of p75 receptor is believed to be an effective tool for the development of new drugs against Alzheimer's disease.

Antonio García y García, O.F.M. (1928–2013)

Antonio Garcia y Garcia, O.F.M, died on July 8, 2013, after a decade of suffering from an agonizing form of Alzheimer's disease, in the Franciscan convent of Chipiona (Cadiz). Born in Bretona (Lugo, Galicia) on January 7, 1928, he joined the Order of St. Francis at the age of eighteen and was ordained a priest in 1952. He received his doctorate in canon law at the Pontificium Athenaeum Antonianum in Rome in 1956 and was appointed professor for History of Canon Law at the Universidad Pontificia de Salamanca in 1959, where he taught until his retirement.With the death of Professor Garcia, the profession has lost one of the last founding fathers of modern scholarship in medieval canon law. He belonged to the group of canonists led by Stephan Kuttner. These canonists were associated by friendship and pointed the way to a manuscript-based research of canon law. They were at the same time great scholars and true gentlemen. He was an amazingly prolific writer, with a scholarly output that surprises in quantity as well as in its wide range of content and interest. His oeuvre includes thirty-two books and almost 300 articles (see his bibliography published in Studia Gratiana 28,1998). The topics of his publications, which appeared in a large variety of Spanish, Portuguese, and international journals, stretch geographically from his own little hometown in Spain to Latin America and chronologically from the sixth to the seventeenth centuries. He critically investigated texts from the canons of the Fourth Lateran Council (1215) to the Tractatus de legibus of Francisco Suarez (1612); he analyzed problems of legal history from the fidelity oaths in Visigothic councils to the human rights of the indigenous people of Latin America; and he discussed the history of the European universities as well as that of the colonial conquests by Spain and Portugal. Among the innumerable findings of his research, two farsighted endeavors stand out, assuring that the international community of historians will remember Father Garcia forever with respect and gratitude. First is the monumental Synodicon Hispanum, which he conceived, directed, and partly compiled. Progressing at a steady pace since 1981, it has produced eleven volumes to date and covered a large number of Spanish and Portuguese dioceses in a systematic fashion, thus placing the two Iberian countries in a leading position within the international scholarship in synodal texts. The second invaluable accomplishment of Father Garcia results from his tireless and most successful efforts to highlight the treasures of medieval manuscripts in Spain. Fifty years ago, the manuscript holdings of that country were regarded, even by native scholars, as a kind of wonderland-immensely rich, but mysterious and practically inaccessible. If this situation has definitely changed by now, at least as far as medieval legal manuscripts are concerned, this is almost entirely due to Father Garcia, who acted as a very efficient access manager to Spanish libraries, operating on two different fronts. …

Getting Rid of Intracellular A&amp;#946; . - Loss of Cellular Degradation Leads to Transfer Between Connected Neurons

The sporadic, late onset form of Alzheimer's disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased β-amyloid (Aβ) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of Aβ. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted Aβ. Furthermore, accumulation of improperly degraded Aβ in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric Aβ can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, Aβ accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of Aβ causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced Aβ clearance and subsequent Aβ spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated Aβ, it can be possible to remove it and avoid Aβ-induced neurodegeneration without disturbing the endogenously important pool of secreted Aβ. Additionally, drugs targeted to inhibit the spread of intracellular toxic Aβ aggregates may also be useful in stopping the progression of pathology, without affecting the level of Aβ that normally occurs in the brain.

Differences in Functional Brain Activation and Hippocampal Volume Among Amnestic Mild Cognitive Impairment Subtypes

Patients with amnestic mild cognitive impairment (aMCI) often display deficits in episodic memory. Amnestic MCI is now recognized as a prodromal form of Alzheimer's disease. Various aMCI clinical subtypes have been identified as ingle-domain (SD) or multi-domain (MD). The various subtypes represent heterogeneous syndrome indicating the probability of progression to AD, impaired cognitive domains and so on. To examine the characteristics of brain regions of aMCI subtypes is likely to be important for early diagnosis and prediction to AD. This study investigated brain functional activation and hippocampal atrophy during a visually complex scene encoding in 20 individuals with aMCI-SD, 14 individuals with aMCI-MD and 25 healthy controls. During the encoding task, aMCI-MD patients had reduced activation in right superior medial frontal, right inferior and middle temporal, right middle occipital and left inferior frontal regions compared to controls. The different active brain regions between aMCI-MD and aMCI-SD patients are the right middle occipital and left middle cingulum regions. The aMCI-MD group had significantly lower left hippocampus volumes compared to the aMCI-SD group and controls, but there was no difference between aMCI-SD patients and the control group in terms of left hippocampus atrophy. The findings provide evidence that aMCI may represent a heterogeneous group. The aMCI-MD patients displayed more severe hippocampcal atrophy and fMRI activation changes than aMCI-SD. The aMCIMD may represent a more advanced prodromal stage of AD.

Alzheimer’s disease: An update of the roles of receptors, astrocytes and primary cilia (Review)

The pathophysiological mechanisms underlying the onset and inexorable progression of the late‑onset form of Alzheimer's disease (AD) are still the object of controversy. This review takes stock of some most recent advancements of this field concerning the complex roles played by the amyloid‑β (Aβ)‑binding p75 neurotrophin receptor (p75NTR) and calcium‑sensing receptor (CaSR) and by the primary cilia in AD. Apart from their physiological roles, p75NTR is more intensely expressed in the hippocampus of human AD brains and Aβ‑bound p75NTR triggers cell death, whereas Aβ‑bound CaSR signalling induces the denovo synthesis and release of nitric oxide (NO), vascular endothelial growth factor (VEGF)‑A and Aβ peptides (Aβs), particularly on the part of normal adult human astrocytes. The latter effect could significantly increase the pool of Aβ‑ and NO‑producing nerve cells favouring the progressive spread of a self‑sustaining and self‑reinforcing 'infectious' mechanism of neural and vascular (i.e. blood-brain barrier) cell damage. Interestingly, primary cilia concentrate p75NTR receptors in their membranes and are abnormally structured/damaged in transgenic (Tg) AD‑model mice, which could impact on the adult neurogenesis occurring in the dentate gyrus's subgranular zone (SGZ) that is necessary for new memory encoding, thereby favouring typical AD cognitive decline. Altogether, these findings may pave the way to novel therapeutic approaches to AD, particularly in its mild cognitive impairment (MCI) and pre‑MCI stages of development.