Non-familial Alzheimer's Disease Research Articles

Tau PET in autosomal dominant Alzheimer's disease: relationship with cognition, dementia and other biomarkers.

Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer's disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer's disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer's disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-β, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer's disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-β. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-β was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer's disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, non-familial Alzheimer's disease.

The antimicrobial protection hypothesis of Alzheimer's disease

ObjectiveWe explore here a novel model for amyloidogenesis in Alzheimer's disease (AD). This new perspective on AD amyloidosis seeks to provide a rational framework for incorporating recent and seemingly independent findings on the antimicrobial role of β-amyloid and emerging experimental, genetic, and epidemiological data, suggesting innate immune-mediated inflammation propagates AD neurodegeneration. BackgroundAD pathology is characterized by cerebral deposition of amyloid-β protein (Aβ) as β-amyloid. Genetic studies have confirmed the key role of Aβ in AD, revealing that mutation-mediated shifts in the peptides generation lead to early onset familial Alzheimer's disease. However, Aβ generation appears normal for the majority of AD patients, who lack early onset familial Alzheimer's disease mutations. In prevailing models of nonfamilial AD, individual genetics and age-associated changes in brain milieu promote an intrinsically abnormal propensity of Aβ for self-association. However, emerging findings are increasingly inconsistent with characterization of Aβ oligomerization as a nonphysiological and exclusively pathological activity. Recent studies suggest Aβ is an ancient, highly conserved effector molecule of innate immunity. Moreover, Aβ oligomerization and β-amyloid generation appear to be important innate immune pathways that mediate pathogen entrapment and protect against infection. New AD amyloidogenesis modelRecent findings on inflammation-mediated neurodegeneration and the role of Aβ in immunity have led to emergence of the “Antimicrobial Protection Hypothesis” of AD. In this model, β-amyloid deposition is an early innate immune response to genuine, or mistakenly perceived, immunochallenge. Aβ first entraps and neutralizes invading pathogens in β-amyloid. Aβ fibrillization drives neuroinflammatory pathways that help fight the infection and clear β-amyloid/pathogen deposits. In AD, chronic activation of this pathway leads to sustained inflammation and neurodegeneration. Mounting data link elevated brain microbe levels with AD. The Antimicrobial Protection Hypothesis reveals how increased brain microbial burden may directly exacerbate β-amyloid deposition, inflammation, and AD progression. Amyloid cascade hypothesisIn the antimicrobial protection model, the modality of Aβ's pathophysiology is shifted from abnormal stochastic behavior toward dysregulated innate immune response. However, β-amyloid deposition in AD still leads to neurodegeneration. Thus, the new model extends but remains broadly consistent with the Amyloid Cascade Hypothesis and overwhelming data showing the primacy of Aβ in AD pathology.

Finding the Middle Ground for Autophagic Fusion Requirements.

Autophagosome/amphisome-lysosome fusion is a highly regulated process at the protein, lipid, and biochemical level. Each primary component of fusion, such as the core SNAREs, HOPS complex, or physical positioning by microtubule-associated dynein motors, are regulated at multiple points to ensure optimum conditions for autophagic flux to proceed. With the complexity of the membrane fusion system, it is not difficult to imagine how autophagic flux defect-related disorders, such as Huntington's disease, non-familial Alzheimer's disease, and Vici syndrome develop. Each membrane fusion step is regulated at the protein, lipid, and ion level. This review aims to discuss the recent developments toward understanding the regulation of autophagosome, amphisome, and lysosome fusion requirements for successful autophagic flux.

Candidate SNP Markers of Familial and Sporadic Alzheimer's Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters.

While year after year, conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010. These diseases are kidney cancer, chronic kidney diseases, liver cancer, diabetes, drug addiction, poisoning cases, consequences of falls, and Alzheimer's disease (AD) as one of the leading pathologies. There are familial AD of hereditary nature (~4% of cases) and sporadic AD of unclear etiology (remaining ~96% of cases; i.e., non-familial AD). Therefore, sporadic AD is no longer a purely medical problem, but rather a social challenge when someone asks oneself: “What can I do in my own adulthood to reduce the risk of sporadic AD at my old age to save the years of my lifespan from the destruction caused by it?” Here, we combine two computational approaches for regulatory SNPs: Web service SNP_TATA_Comparator for sequence analysis and a PubMed-based keyword search for articles on the biochemical markers of diseases. Our purpose was to try to find answers to the question: “What can be done in adulthood to reduce the risk of sporadic AD in old age to prevent the lifespan reduction caused by it?” As a result, we found 89 candidate SNP markers of familial and sporadic AD (e.g., rs562962093 is associated with sporadic AD in the elderly as a complication of stroke in adulthood, where natural marine diets can reduce risks of both diseases in case of the minor allele of this SNP). In addition, rs768454929, and rs761695685 correlate with sporadic AD as a comorbidity of short stature, where maximizing stature in childhood and adolescence as an integral indicator of health can minimize (or even eliminate) the risk of sporadic AD in the elderly. After validation by clinical protocols, these candidate SNP markers may become interesting to the general population [may help to choose a lifestyle (in childhood, adolescence, and adulthood) that can reduce the risks of sporadic AD, its comorbidities, and complications in the elderly].

Loss of functional connectivity is greater outside the default mode network in nonfamilial early-onset Alzheimer's disease variants

The common and specific involvement of brain networks in clinical variants of Alzheimer's disease (AD) is not well understood. We performed task-free (“resting-state”) functional imaging in 60 nonfamilial AD patients, including 20 early-onset AD (age at onset <65 years, amnestic/dysexecutive deficits), 24 logopenic aphasia (language deficits), and 16 posterior cortical atrophy patients (visual deficits), as well as 60 healthy controls. Seed-based connectivity analyses were conducted to assess differences between groups in 3 default mode network (DMN) components (anterior, posterior, and ventral) and 4 additional non-DMN networks: left and right executive-control, language, and higher visual networks. Significant decreases in connectivity were found across AD variants compared with controls in the non-DMN networks. Within the DMN components, patients showed higher connectivity in the anterior DMN, in particular in logopenic aphasia. No significant differences were found for the posterior and ventral DMN. Our findings suggest that loss of functional connectivity is greatest in networks outside the DMN in early-onset and nonamnestic AD variants and may thus be a better biomarker in these patients.

Differences between Familial and Non-Familial Early Onset Alzheimer's Disease (P05.045)

Objective: To investigate neurological differences between Non-familial EAD and PSEN1, the most common FAD, as markers for FAD. Background Although familial Alzheimer9s disease (FAD) is an Early onset AD (EAD), most patients with EAD do not have a familial disorder. Recent guidelines recommend obtaining genetic testing only in those EAD patients with 2 first-degree relatives. However, some patients with FAD may lack a known family history or other indications for suspecting FAD but might nonetheless be FAD mutation carriers and the results of such testing helpful to clinicians and families. Design/Methods: Retrospective chart review of a large University-based cohort of patients with non-familial early-onset AD (n=75) and with PSEN1-related AD (n=31). Results: There were group differences in age of onset, with PSEN1 mutation carriers being significantly younger, and in disease severity/duration (p Conclusions: In addition to a much younger age of onset, clinicians may be able to recognize FAD patients with PSEN1 mutations by specific abnormalities on the neurological history and examination. In some contexts, these findings should lead to genetic counseling and appropriate recommendations for obtaining PSEN1 testing or other genetic tests for FAD. Supported by: PHS K08 AG-22228, California DHS #04-35522, Alzheimer9s Disease Research Center Grant P50 AG-16570 from the National Institute on Aging, the Easton Consortium for Alzheimer9s Disease Drug Discovery and Biomarkers, the Sidell Kagan Foundation, the Shirley and Jack Goldberg Trust and Veteran9s Affairs Merit award. Disclosure: Dr. Joshi has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Ringman has received personal compensation for activities with Takeda Pharmaceuticals as a scientific advisory board member.Dr. Ringman has received research support from Wyeth, Elan, Janssen, Bristol-Myers Squibb, Medivation, and Pfizer Pharmaceuticals. Dr. Juarez has nothing to disclose. Dr. Mendez has nothing to disclose.

Apolipoprotein E, amyloid-ß clearance and therapeutic opportunities in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by extracellular amyloid-ß (Aß) and intraneuronal tau protein brain pathologies. The most significant risk factor for non-familial AD is the presence of the E4 isoform of the cholesterol transporter apolipoprotein E (apoE). Despite extensive basic research, the exact role of apoE in disease aetiology remains unclear. Correspondingly, therapeutic targeting of apoE in AD is at an early preclinical stage. In this review, I discuss the key interactions of apoE and Aß pathology, the current progress of preclinical animal models and the caveats of existing therapeutic approaches targeting apoE. Finally, novel Alzheimer's genetics and Aß-independent disease mechanisms are highlighted.

Modulators of Cytoskeletal Reorganization in CA1 Hippocampal Neurons Show Increased Expression in Patients at Mid-Stage Alzheimer's Disease

During the progression of Alzheimer's disease (AD), hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB) III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB), mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression.

Impact of APOE status on cognitive maintenance in healthy elderly persons

The epsilon4 allele, a variant of the apolipoprotein E (ApoE) gene, is the most prominent genetic risk factor for sporadic, non-familial Alzheimer's disease (AD) currently known. We investigated the impact of the ApoE-epsilon4 status on cognitive performance at repeated test administration in elderly non-symptomatic persons, with a specific focus on practice effects. Three hundred and fifty-five physically and mentally healthy participants of the Basel Study on the Elderly (119 F, 236 M; age 68.3 +/- 7.6; years of education 12.7 +/- 3.1; Mini-Mental State scores 29.0 +/- 1.0) were grouped into ApoE epsilon4 carriers and ApoE epsilon4 non-carriers (36.9% and 63.1% of the sample, respectively). Participants were assessed at the beginning of the longitudinal study and on average two years later by means of the California Verbal Learning Test (CVLT) and the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB), a multidimensional cognitive test battery. Baseline and change scores were analyzed with multiple regression procedures and adjusted for age, education and gender; change scores were also adjusted for baseline performance. The ApoE epsilon4 non-carriers showed slightly better performance with regard to most cognitive parameters at baseline. Mean practice effects of the ApoE epsilon4 non-carriers in 12 out of 13 CVLT variables and in five out of the nine main CERAD-NAB variables were above the 50th percentile, while those of the ApoE epsilon4 carriers were below the 50th percentile in the respective distributions of test-retest change scores. The epsilon4 allele of the ApoE gene has a negative impact on cognitive performance, notably on episodic memory functions, in physically and mentally healthy aged persons. Practice effects seen in carriers of the ApoE epsilon4 were inferior in most areas tested to the effects seen in ApoE epsilon4 non-carriers. Further follow-up of these subjects will help to determine the clinical significance of these findings.

Four subgroups of Alzheimer's disease based on patterns of atrophy using VBM and a unique pattern for early onset disease

To clarify the involvement of the posterior cingulate cortex (PCC) in Alzheimer's disease (AD), we analyzed brain volume loss by voxel-based morphometry. Forty patients with non-familial AD and 20 patients with mild cognitive impairment (MCI) were recruited and compared to 88 elderly volunteers and 40 young volunteers. Local atrophy with aging was observed bilaterally in the perisylvian opercula, anterior cingulate cortex, caudate head, dorsomedial thalamus and parahippocampal cortex. In addition to those, atrophy in AD patients was observed in the amygdala, hippocampus, subcallosal region, posterior-associated cortices and PCC. We classified AD into four subgroups according to the atrophy pattern; atrophy in the amygdala/hippocampal formations (Hipp), in the Hipp and posterior cortices, in the Hipp and PCC and in the PCC and posterior cortices (PCC/-TOPa). As a result, the probability of PCC/-TOPa was 90% for ages < 65 years, whereas that of the Hipp was 100% for disease duration > 36 months. PCC atrophy was found in 16 of 40 AD patients and eight of 20 MCI patients. There seemed to be two subgroups with atrophy of the PCC, the one with disease progression and the other without. The latter had characteristic features of early onset and no significant atrophy in the amygdala/anterior hippocampus. There are at least four atrophy patterns that raise doubts about a single disease entity or progression in AD. This may reflect a different hierarchical pattern of progression in patients who have atrophy in PCC and posterior cortices when compared to the Braak staging scheme.

Aberrant accentuation of neurofibrillary degeneration in the hippocampus of Alzheimer's disease with amyloid precursor protein 717 and presenilin-1 gene mutations

This study reports correlation of the hippocampal neurofibrillary tangles (NFT) density with beta-amyloid (Aβ) precursor protein (APP) 717 mutation, presenilin (PS)-1 mutation and apolipoprotein E (Apo-E) e4 alleles (E4), being graded as 3 forms (no-E4, one-E4 and two-E4) in autopsied brains from patients with familial and non-familial Alzheimer's disease (AD). We studied the density of NFT-free neurons, intracellular NFT (I-NFT), extracellular NFT (E-NFT) and total NFT (I-NFT plus E-NFT) in the six hippocampal subdivisions: cornu ammonis (CA) 1–CA4, subiculum and entorhinal cortex. The APP mutation cases showed significantly higher total NFT density in the CA1–CA2 region, and the PS-1 mutation cases also showed higher density of total NFT in the CA1–CA3 than non-familial cases. Moreover, high densities of the E-NFT contributed to these high total NFT densities. Non-familial AD cases showed a stereotypical NFT distribution with entorhinal accentuation in the hippocampus irrespective of E4 frequency. Thus, APP and PS-1 mutations predominantly affect the CA regions with profound neurodegeneration, which contributes early and severe clinical features of familial AD.

Diagnostic challenges of using CSF assay of tau and beta-amyloid42 in atypical degenerative dementias of the Alzheimer type

This report presents three cases of atypical degenerative dementias in order to illustrate challenges associated with the use of biologic markers of Alzheimer's disease (AD) for diagnosis and management. Clinical diagnostic methods followed the NINCDS-ADRDA criteria for AD. Additional diagnostic studies included serial neurocognitive testing, MRI, neuroSPECT, ApoE genotyping, and a CSF assay of tau and beta-amyloid(42). For patient 1, both the clinical and biologic markers were consistent with AD. The patient was diagnosed with AD with a high degree of confidence, even though the base rate of nonfamilial AD at this age group (<55 years) is exceedingly rare. This case argues favorably for the use of biologic markers to aid in confirming a diagnosis in an atypical dementia. Patient 2 met the NINCDS-ADRDA criteria for AD, although with less confidence. Neurocognitive data indicated a progressive right hemispheric syndrome, insight was preserved, and ApoE was 3/3, but tau concentrations and beta-amyloid(42) were highly consistent with cut-offs for AD; the differential fell on the Pick's disease/frontotemporal degeneration spectrum. Patient 3 had no clinical evidence of the disease, even when evaluated via extensive neurocognitive testing over a 2-year interval. However, ApoE was 4/4, and CSF assay of tau and beta-amyloid(42) were within the AD range. Therefore, while the CSF assay of tau and beta-amyloid(42) markers was confirmatory of AD, each case was highly atypical. Results illustrate the lack of normative data available when using biologic markers for highly atypical cases, calling into question their usefulness for such patients. These cases illustrate the interplay between neuropsychological and biological markers in establishing neurodegenerative diagnoses.

Are children of older fathers at risk for genetic disorders?

Genetic risks related to paternal age should be of interest to clinical andrologists counselling older men who wish to father a child. Theoretically, the number of (pre-meiotic) mitotic cell divisions during spermatogenesis and their remarkable increase with ageing compared with oogenesis would be in favour of genetic risks for the offspring of older men. But for numerical and structural chromosomal anomalies, such an influence of paternal age has not been found. However, in several autosomal dominant disorders affecting three specific genes (fibroblast growth factor receptor 2 and 3, RET proto-oncogene) the risk for a child to be affected increases with paternal age at time of birth. For other autosomal dominant -X chromosomal dominant or recessive disorders, the available data are sufficient to support the concept of a positive relationship between paternal age and de novo gene mutations. Studies analysing gene sequences of affected children and their parents would allow further evaluation of this topic. The impact of paternal age on disorders with a complex genetic background, however, is a matter of debate. A significant effect of paternal age could not be shown for nonfamilial Alzheimer's disease, congenital heart defects, nonfamilial schizophrenia, acute lymphoblastic leukaemia or prostate cancer.

Non-familial Alzheimer's disease is mainly due to genetic factors.

This team takes the position that what is commonly referred to as non-familial Alzheimer's disease (AD) is predominantly due to genetic factors. Population-based studies suggest that genetic factors cause the majority of cases that begin after age 60. There are several lines of evidence supporting this position: Data from the Nun Study suggest that the risk for AD is largely established by early adulthood, implying that later adult exposures likely play only a small role in causation. Family studies show that first-degree blood relatives of persons with non-familial AD have a substantially increased risk of AD relative to controls. Twin studies suggest that the heritability of AD exceeds 60%. Environmental factors, such as socioeconomic status, education, and head injury, are strong risk factors for AD only in individuals with a genetic predisposition. The APOE genotype is a powerful risk factor for AD and accounts for as much as 50%. There are numerous other candidate genes with strong associations with AD that presumably explain the remaining population risk. This paper further reviews the mechanisms associated with AD causation for APOE and other candidate genes and implications for the development of prevention strategies.

You can take the genome out of the organism, but can you take the organism out of the environment?

In a debate held on July 28th in Cincinnati, a new chapter in the nature versus nurture saga was initiated. The premise under discussion was whether nonfamilial, i.e. sporadic, Alzheimer disease (AD) is primarily a genetic disorder. The participants took the position that either A) genetic factors are largely responsible for the so-called sporadic cases of AD or B) environmental factors contribute to the development of sporadic AD. The argument that genetic factors result in sporadic AD was based on population based studies such as the Nun study and twin studies. The participants correctly point out the more than passing role of the APOE-e4 in the development of Alzheimer disease. In addition, a wide variety of genes and chromosomal loci have been implicated in the development of Alzheimer disease. However, although twin studies, for example, indicate a heritability of greater than 60% it is not 100%. The typical argument employed to explain this type of discrepancy is that when age corrected we get much closer since one of the siblings may die of other causes before having the “opportunity” to develop Alzheimer disease. While admitting that diet and other health related activities may influence the development of Alzheimer disease they maintain their position that non-familial Alzheimer disease is largely the result of genetics. On the other hand, the other participants argue that non-genetic factors play an important role in nonfamilial Alzheimer disease. Some of the possible factors include viruses, dietary components and metals. The unifying feature is postulated to be inflammation resulting from any of these insults. Special attention was paid to the role of aluminum, which has long been conjectured to facilitate the development of Alzheimer disease. In addition, the role of diet and especially dietary fats were discussed. With the increasing evidence of oxidative stress in the etiology of Alzheimer disease, the authors also consider the role of trace metal deposition through dietary exposure. Finally, increasing evidence in a number of chronic conditions has implicated bacterial and viral pathogens as underlying components in disease etiology. HSV-1 has been implicated as a potential underlying component in Alzheimer disease. Thus, these authors hold that environmental concerns play a large role in the development of Alzheimer disease and moreover are more tractable to intervention that are genetic predispositions. So, what can we take away from this? It is clear that genetic predisposition is important in the development of disease and that the development of disease can be modified by controlling external influences, i.e. cholesterol uptake. However, the important issue from the perspective of the prospective patient, current patient, or family members is what can we predict about the natural history of the individual. The studies listed

Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer's disease.

Cerebral white matter lesions in Alzheimer's disease (AD) consist of subcortical degeneration and ischaemic-hypoxic changes. Glial changes are intimately associated with the white matter lesions, and regressive changes in astrocytes and loss of oligodendroglial cells have been reported. We quantitatively compared glial changes including apoptosis and enhanced lysosomal activity in the frontal and temporal white matter by using terminal dUTP nick end labelling (TUNEL) and immunohistochemistry for glial markers, lysosomes and apoptosis-regulating proteins in non-familial AD brains. The degree of myelin pallor and axonal loss varied considerably in both the frontal and temporal white matter but fibrillary gliosis in demyelinated lesions tended to be less prominent in the temporal white matter in AD cases. A morphometric study with planimetric methods for cross-sectional areas of frontal and temporal white matter revealed that the white matter of AD cases manifested atrophy with significant reduction in frontal (11.9%) and temporal (29.4%) white matter compared to normal controls. Double immunolabelling for glial fibrillary acidic protein (GFAP) and KP1 (CD68) revealed KP1-positive fragmented structures within the weakly GFAP-labelled astrocytes. These KP1-positive structures correspond to process fragmentation and cytoplasmic vacuoles, which in turn indicate enhanced lysosomal activity during regressive changes in astrocytes. The KP1-modified astrocytes were not found in Pick's disease and corticobasal degeneration. The density of apoptotic glial cells, largely oligodendroglial, was significantly higher in the temporal than in the frontal white matter, and most GFAP-positive astrocytes with regressive changes were apoptotic. GFAP-positive astrocyte density was statistically the same in the frontal and temporal white matter, but the density of KP1-modified astrocytes was higher in the temporal than in the frontal white matter. The rate of white matter shrinkage was significantly correlated with the density of apoptotic glial cells and the density of KP1-modified astrocytes in the temporal lobe in AD cases. An increase in apoptotic glial cell density was found to contribute to GFAP-positive astrocytes with regressive changes in temporal white matter, while apoptosis of vascular smooth muscle cells did not show topographical accentuation. Astrocytes labelled with beta amyloid protein were not apoptotic, and the density of apoptotic cells labelled with CD95 and caspase-3 was too low in both types of white matter to be statistically evaluated. Our results imply that regressive changes in astrocytes and glial apoptosis are, to some extent, associated with white matter lesions, particularly of the temporal lobe in AD brains. The presence of apoptotic astrocytes with evidence of regressive change could therefore be a histological hallmark for white matter degeneration in AD.

Progressive decrease of amyloid precursor protein carboxy terminal fragments (APP-CTFs), associated with tau pathology stages, in Alzheimer's disease.

Amyloid precursor protein (APP) dysfunction is a key aetiologic agent in Alzheimer's disease (AD). The processing of this transmembrane protein generates carboxy terminal fragments (CTFs) upstream of beta-amyloid peptide (Abeta) production. The physiologic significance of APP-CTFs is still poorly understood, as well as the relationship that could link APP dysfunction and tau pathology in familial and non-familial AD (non-FAD). In the present study, we have investigated the quantitative and qualitative changes of APP-CTFs in different brain areas of non-demented and demented patients from a prospective and multidisciplinary study. A significant decrease of the five APP-CTFs was observed, which correlated well with the progression of tau pathology, in most cases with infraclinical AD and AD, either familial or non-FAD. Furthermore, solubility properties and the ratio between the five bands were also modified, both in the Triton-soluble and/or -insoluble fractions. Together, we show here for the first time a modification directly observed on APP-CTFs upstream of Abeta products and its relationship with tau pathology, which could reflect the basic aetiological mechanisms of AD.

Are dopamine receptor agonists neuroprotective in Parkinson's disease?

Dopamine receptor agonists are playing an increasingly important role in the treatment of not only patients with advanced Parkinson's disease and those with levodopa-induced motor fluctuations, but also in the early treatment of the disease. This shift has been largely due to the demonstrated levodopa-sparing effect of dopamine agonists and their putative neuroprotective effect, with evidence for the latter being based largely on experimental in vitro and in vivo studies. In this article we review the evidence for neuroprotection by the dopamine agonists pramipexole, ropinirole, pergolide, bromocriptine and apomorphine in cell cultures and animal models of injury to the substantia nigra. Most of the studies suggest that dopamine agonists may have neuroprotective effects via direct scavenging of free radicals or increasing the activities of radical-scavenging enzymes, and enhancing neurotrophic activity. However, the finding that pramipexole can normalise mitochondrial membrane potential and inhibit activity of caspase-3 in cytoplasmic hybrid cells derived from mitochondrial DNA of patients with nonfamilial Alzheimer's disease suggests an even broader implication for the neuroprotective role of dopamine agonists. Although the clinical evidence for neuroprotection by dopamine agonists is still limited, the preliminary results from several ongoing clinical trials are promising. Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progression of Parkinson's disease using various surrogate markers of neuronal degeneration such as 18F-levodopa positron emission tomography and 123I beta-CIT (carbomethoxy-beta-4-iodophenyl-nortropane) single positron emission computed tomography. The results of these experimental and clinical studies will improve our understanding of the action of dopamine agonists and provide critical information needed for planning future therapeutic strategies for Parkinson's disease and related neurodegenerative disorders.

Inhibition of the ubiquitin-proteasome system in Alzheimer's disease.

Alzheimer's disease is the most common cause of dementia in the elderly. Although several genetic defects have been identified in patients with a family history of this disease, the majority of cases involve individuals with no known genetic predisposition. A mutant form of ubiquitin, termed Ub(+1), has been selectively observed in the brains of Alzheimer's patients, including those with nonfamilial Alzheimer's disease, but it has been unclear why Ub(+1) expression should be deleterious. Here we show that Ub(+1) is an efficient substrate for polyubiquitination in vitro and in transfected human cells. The resulting polyubiquitin chains are refractory to disassembly by deubiquitinating enzymes and potently inhibit the degradation of a polyubiquitinated substrate by purified 26S proteasomes. Thus, expression of Ub(+1) in aging brain could result in dominant inhibition of the Ub-proteasome system, leading to neuropathologic consequences.

Alzheimer's disease cybrids replicate ?-amyloid abnormalities through cell death pathways

Alzheimer's disease (AD) is characterized by the deposition in brain of beta-amyloid (Abeta) peptides, elevated brain caspase-3, and systemic deficiency of cytochrome c oxidase. Although increased Abeta deposition can result from mutations in amyloid precursor protein or presenilin genes, the cause of increased Abeta deposition in sporadic AD is unknown. Cytoplasmic hybrid ("cybrid") cells made from mitochondrial DNA of nonfamilial AD subjects show antioxidant-reversible lowering of mitochondrial membrane potential (delta(gYm), secrete twice as much Abeta(1-40) and Abeta(1-42), have increased intracellular Abeta(1-40) (1.7-fold), and develop Congo red-positive Abeta deposits. Also elevated are cytoplasmic cytochrome c (threefold) and caspase-3 activity (twofold). Increased AD cybrid Abeta(1-40) secretion was normalized by inhibition of caspase-3 or secretase and reduced by treatment with the antioxidant S(-)pramipexole. Expression of AD mitochondrial genes in cybrid cells depresses cytochrome c oxidase activity and increases oxidative stress, which, in turn, lowers delta(psi)m. Under stress, cells with AD mitochondrial genes are more likely to activate cell death pathways, which drive caspase 3-mediated Abeta peptide secretion and may account for increased Abeta deposition in the AD brain. Therapeutic strategies for reducing neurodegeneration in sporadic AD can address restoration of delta(psi)m and reduction of elevated Abeta secretion.