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The pathogenesis of Alzheimer’s disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain’s vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer’s disease. OS and Aβ are linked to each other because Aβ induces OS, and OS increases the Aβ deposition. Thus, the answer to the question “which comes first: the chicken or the egg?” remains extremely difficult. In any case, the evidence for the primary occurrence of oxidative stress in AD is attractive. Thus, evidence indicates that a long period of gradual oxidative damage accumulation precedes and results in the appearance of clinical and pathological AD symptoms, including Aβ deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline. Moreover, oxidative stress plays a crucial role in the pathogenesis of many risk factors for AD. Alzheimer’s disease begins many years before its symptoms, and antioxidant treatment can be an important therapeutic target for attacking the disease.

Neuroinflammation is involved in the pathogenesis of Alzheimer's disease, and the transcription factor NF-kappa B is a player in this event. We found here that the ischemic damage alone or in association with A beta(1-42) activates the NF-kappa B pathway, induces an increase of BACE1 and a parallel inhibition of Uch-L1 and TREM2, both in vitro and in vivo, in Tg 5XFAD and in human brains of sporadic AD. This mechanism creates a synergistic loop that fosters inflammation. We also demonstrated a significant protection exerted by the restoration of Uch-L1 activity. The rescue of the enzyme is able to abolish the decrease of TREM2 and the parameters of neuroinflammation.

We applied RT-QuIC assay to detect α-synuclein aggregates in cerebrospinal fluid (CSF) of patients with suspected Creutzfeldt–Jakob disease who had a neuropathological diagnosis of dementia with Lewy bodies (DLB) (n=7), other neurodegenerative diseases with α-synuclein mixed pathology (n=20), or without Lewy-related pathology (n=49). The test had a sensitivity of 92.9% and specificity of 95.9% in distinguishing α-synucleinopathies from non-α-synucleinopathies. When performed in the CSF of patients with DLB (n=36), RT-QuIC was positive in 17/20 with probable DLB, 0/6 with possible DLB, and 0/10 with Alzheimer disease. These results indicate that RT-QuIC for α-synuclein is an accurate test for DLB diagnosis.

Alzheimer's disease may mimic frontotemporal dementia. We describe a case of presenile dementia who presented with peudo-psychotic symptoms carrying a PSEN1 mutation (P355 S), which was not known to be pathogenic. PET-FDG showed bilateral frontotemporal hypometabolism, but at MRI, multiple microbleeds were detected, suggestive of amyloid angiopathy.

Summary The mechanistic relationship between amyloid β1‐42 (Aβ1‐42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1‐42 monomers and oligomers on Tau, using mice expressing wild‐type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1‐42, mice were sacrificed after 3 h or 4 days. The short‐lasting treatment with Aβ monomers, but not oligomers, showed a conformational PHF‐like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aβ monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aβ oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aβ1‐42 monomers foster synaptic activity. Our results suggest that Aβ monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti‐Aβ therapies should be targeted to Aβ1‐42 monomers too.

It is now established that cholesterol oxidation products (oxysterols) are involved in several events underlying Alzheimer's disease (AD) pathogenesis. Of note, certain oxysterols cause neuron dysfunction and degeneration but, recently, some of them have been shown also to have neuroprotective effects. The present study, which aimed to understand the potential effects of 24-hydroxycholesterol (24-OH) against the intraneuronal accumulation of hyperphosphorylated tau protein, stressed these latter effects. A beneficial effect of 24-OH was demonstrated in SK-N-BE neuroblastoma cells, and is due to its ability to modulate the deacetylase sirtuin 1 (SIRT1), which contributes to preventing the neurotoxic accumulation of the hyperphosphorylated tau protein. Unlike 24-OH, 7-ketocholesterol (7-K) did not modulate the SIRT1-dependent neuroprotective pathway. To confirm the neuroprotective role of 24-OH, in vivo experiments were run on mice that express human tau without spontaneously developing tau pathology (hTau mice), by means of the intracerebroventricular injection of 24-OH. 24-OH, unlike 7-K, was found to completely prevent the hyperphosphorylation of tau induced by amyloid β monomers. These data highlight the importance of preventing the loss of 24-OH in the brain, and of maintaining high levels of the enzyme SIRT1, in order to counteract neurodegeneration. Graphical abstract: A hypothetical scheme of the molecular mechanisms underlying the effects of 24-OH on hyperphosphorylated tau accumulation.fx1 Keywords: 24-hydroxycholesterol, Sirtuin 1, Tau, Oxysterols, Alzheimer's disease

Amyloid-β (Aβ) has been proposed as a biomarker and a drug target for the therapy of Alzheimer's disease (AD). The neurotoxic entity and relevance of each conformational form of Aβ to AD pathology is still under debate; Aβ oligomers are considered the major killer form of the peptide whereas monomers have been proposed to be involved in physiological process. Here we reviewed some different effects mediated by monomers and oligomers on mechanisms involved in AD pathogenesis such as autophagy and tau aggregation. Data reported in this review demonstrate that Aβ monomers could have a major role in sustaining the pathogenesis of AD and that AD therapy should be focused not only in the removal of oligomers but also of monomers.

The mechanism of tau toxicity is still unclear. Here we report that recombinant tau oligomers and monomers, intraventricularly injected in mice with a pure human tau background, foster tau pathology through different mechanisms. Oligomeric forms of tau alter the conformation of tau in a paired helical filament-like manner. This effect occurs without tau hyperphosphorylation as well as activation of specific kinases, suggesting that oligomers of tau induce tau assembly through a nucleation effect. Monomers, in turn, induce neurodegeneration through a calpain-mediated tau cleavage that leads to accumulation of a 17 kDa neurotoxic peptide and induction of apoptotic cell death.

People affected by dementia experienced decreased life expectancy with a 2-4 times higher risk of death at a given age compared to non-demented people. Dementia represents a major cost to health care and society in the Western world and, particularly in Italy, is projected to become a high-resource demanding chronic disease. The present study aimed to estimate the average survival rate of a group of community dwelling elderly affected by dementia in Italy, and to assess the predictive variables associated with survival length. This retrospective study collected the data of patients (n = 290) who died from 2008 to 2012. The data were extracted from a cohort of over 2,000 patients from three outpatient Dementia Clinics of Genoa (Italy). Demographic data and other clinical parameters listed in the patients' clinical records were collected. The mean survival rate after dementia diagnosis was 3.3 ± 0.1 years, lower compared to the age-matched healthy population. The survival rate of these patients showed a significant correlation with age (n = 290; r = -0.16: p < 0.006), with the cognitive status (n = 285; r = 0.16: p < 0.007), with education (n = 204; r = 0.23: p < 0.001), with comorbidity (n = 138; r = -0.41: p < 0.0001), with depressive mood (n = 74; r = 0.44: p < 0.0001), and with the functional status (ADL: n = 242, r = 0.29: p < 0.0001; IADL: n = 243; r = 0.25: p < 0.0001). Multivariate regression revealed age, gender, and functional status as the main determinants informing patient survival. The study provides interesting and reliable data on the pivotal value of early dementia diagnosis in predicting longer survival and addresses comprehensive geriatric assessment, which encompasses most of the predictive variables provided by the study, as a remarkable tool in estimating life expectancy of patients with dementia.

Amyloid-β 1-42 accumulation is the major pathogenetic event in Alzheimer's disease (AD), believed to be responsible for synaptic dysfunction and neuronal cell death. However, the physiologic activity of Aβ peptides remains elusive: Aβ might not only play a toxic role, but also act as a functional signaling intermediate. We recently reported that Aβ1-42 promotes BACE1 transcription through the activation of the JNK-c-jun pathway. Here, we show that the Aβ1-42-mediated increase in BACE1 expression is accompanied by a decrease in ubiquitin C-terminal hydrolase L1 (Uch-L1) expression and activity in different cellular models such as neuroblastoma SH-SY5Y as well as NT(2) neuronal cells. We also found that the increase in BACE1 and the decrease in Uch-L1 are related events and depend on NF-κB pathway; thus, Aβ1-42 is able to activate NF-κB pathway and the pretreatment with a pharmacological inhibitor, able to block the nuclear translocation of the transactivating unit p65, almost completely prevents both the decrease in Uch-L1 and the increase in BACE1 expression. In addition, the decrease in Uch-L1 activity interferes with the lysosomal degradation of BACE1, as demonstrated by the decrease in Cathepsin D activity and the partial accumulation of BACE1 in lysosomes after Aβ1-42 treatment as well after Uch-L1 inhibition. In support of the in vitro data, we observed low protein levels of Uch-L1 associated with high protein levels of BACE1 in sporadic AD brains. Our data suggest that Uch-L1 could be an attractive target for the development of new therapeutic approaches for AD.

J. Neurochem. (2012) 122, 1023–1031. Abstract The pathogenesis of Alzheimer’s disease (AD) is only partially understood. β-amyloid (Aβ) is physiologically generated by sequential cleavage of its precursor protein by the β- and the γ-secretase and it is normally disposed of. In Alzheimer’s disease, Aβ is excessively produced or less dismissed, but the hypothesis on its physiological and pathological role are heterogeneous and often discordant. It has been described a positive feedback loop from the γ- to the β-secretase cleavages of Aβ precursor protein, which is activated by mutations of Presenilin 1 (PS1), the catalytic core of the γ-secretase. These findings show that Aβ precursor protein as well the activity of the γ-secretase are required to obtain the up-regulation of β-secretase which is induced by Presenilin 1 mutations. Then, Aβ 1-42 is the Aβ precursor protein derivative that up-regulates the expression of β-secretase, and c-jun N-terminal kinase (JNK)/c-Jun and ERK1/2 are involved. Here, we describe the activation of β-secretase and c-jun N-terminal kinase related proteins by monomeric Aβ 1-42, defining the conditions that most efficiently strike the described signaling without producing toxicity. Taken together these data imply that monomeric Aβ 1-42, at non-toxic concentrations and time frames, are able to induce a signaling pathway that leads to transcriptional activation of β-secretase.

The sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the amyloid-β protein precursor (AβPP) result in the production of the amyloid-β (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of small, soluble aggregates of Aβ42 is the major pathogenic event of Alzheimer's disease (AD). However, the physiologic activity of Aβ peptides is still elusive. Here, we show that expression of BACE1 is regulated by Aβ42, which augments BACE1 gene transcription through the JNK/c-jun signaling pathway. Of note, Aβ40 has much less effect on BACE1 expression. These findings unveil a positive feedback loop in which γ-secretase cleavage of AβPP releases a functionally-active peptide, Aβ42, that promotes BACE1 transcription. Thus, gene expression induced by Aβ42 may have implications in the neuronal dysfunction and degeneration that occurs in AD.

Mild cognitive impairment is often considered a transitional condition prodromal to Alzheimer's disease. The dissection of genetic risk factors predisposing to mild cognitive impairment is paramount to assess the individual predisposition and reliably evaluate the effectiveness of early therapeutic interventions. We designed a cross-sectional analysis to test whether the occurrence of mild cognitive impairment is influenced by variations of the tau protein gene. The genotypes of seven polymorphisms tagging the major tau haplotypes were assayed on 186 patients with amnestic mild cognitive impairment and 191 unrelated controls. Association study was conducted by logistic regression including APOE genotype and age as covariates. Case-control analysis showed that the common H1 haplotype is significantly overrepresented in patients (OR, 95% CI: 2.31, 1.52-3.51; p

It is now established that oxidative stress is one of the earliest, if not the earliest, change that occurs in the pathogenesis of Alzheimer's disease (AD). Consistent with this, mild cognitive impairment (MCI), the clinical precursor of AD, is also characterized by elevations in oxidative stress. Since such stress does not operate in vacuo, in this study we sought to determine whether redox-active iron, a potent source of free radicals, was elevated in MCI and preclinical AD as compared to cognitively-intact age-matched control patients. Increased iron was found at the highest levels both in the cortex and cerebellum from the pre-clinical AD/MCI cases. Interestingly, glial accumulations of redox-active iron in the cerebellum were also evident in preclinical AD patients and tended to increase as patients became progressively cognitively impaired. Our findings suggests that an imbalance in iron homeostasis is a precursor to the neurodegenerative processes leading to AD and that iron imbalance is not necessarily unique to affected regions. In fact, an understanding of iron deposition in other regions of the brain may provide insights into neuroprotective strategies. Iron deposition at the preclinical stage of AD may be useful as a diagnostic tool, using iron imaging methods, as well as a potential therapeutic target, through metal ion chelators.

Tau hyperphosphorylation appears to be a critical event leading to abnormal aggregation and disrupted function of tau in affected neurons in Alzheimer's disease (AD). As a prominent early event during AD pathogenesis, oxidative stress is believed to contribute to tau phosphorylation and the formation of neurofibrillary lesions. However, acute oxidative stress has disparate effects on tau phosphorylation. Given the chronic nature of AD, in this study, we aimed to determine the long-term effect of oxidative stress on tau phosphorylation. In this regard, we established a novel in vitro model of chronic oxidative stress through inhibition of glutathione (GSH) synthesis with BSO. We confirmed that these cells were under a chronic mild oxidative stress by looking at oxidative response, the induction of heme oxygenase 1 (HO-1) without neuronal death. Chronic oxidative stress increased levels of tau phosphorylated at PHF-1 epitope (serine 399/404) in a time-dependent manner. Our data further suggest that increased activity of JNK and p38 and decreased activity of PP2A are likely involved in chronic oxidative stress-induced tau phosphorylation. In conclusion we suggest that chronic oxidative stress contributes to increased tau phosphorylation in vitro and could play a critical role in neurofibrillary pathology in vivo.

With an ever growing population of aged individuals who are at risk of developing Alzheimer disease (AD), there is an urgent need for a sensitive, specific, and preferably non-invasive diagnostic standard of disease progression. Mainstream thinking suggests that early intervention is key to maximizing the opportunity for a successful treatment regimen in AD and, as such, an early and accurate means of diagnosis is essential. In this study, we applied a recently described antibody-antigen dissociation technique to samples obtained as part of a population-based analysis of the prevalence of AD. Stratified sampling and random selection strategies were combined to obtain a representative population for screening of individuals older than 55 years. Serum antibodies to amyloid-beta (Abeta)(1-42) were measured before and after antigen dissociation. The difference between the two measurements was indicated as the dissociation delta (Delta). Our analyses showed that the levels of dissociated antibody in AD patients were always significantly different from controls and that levels of Abeta antibody after dissociation, but not those of non-dissociated antibody, correlated negatively (p

Mutations of the presenilin 1 (PS1) gene are the most common cause of early onset familial Alzheimer disease (FAD). PS1 mutations alter the activity of the gamma-secretase on the beta-amyloid precursor protein (APP), leading to selective overproduction of beta-amyloid (Abeta) 42 peptides, the species that forms oligomers that may exert toxic effects on neurons. Here we show that PS1 mutations, expressed both transiently and stably, in non-neuronal and neuronal cell lines increase the expression and the activity of the beta-secretase (BACE1), the rate-limiting step of Abeta production. Also, BACE1 expression and activity are elevated in brains of PS1 mutant knock-in mice compared with wild type littermates as well as in cerebral cortex of FAD cases bearing various PS1 mutations compared with in sporadic AD cases and controls. The up-regulation of BACE1 by PS1 mutations requires the gamma-secretase cleavage of APP and is proportional to the amount of secreted Abeta42. Abeta42, and not AICD (APP intracellular domain), is indeed the APP derivative that mediates the overexpression of BACE1. The effect of PS1 mutations on BACE1 may contribute to determine the wide clinical and pathological phenotype of early onset FAD.

A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.

Mitochondrial abnormalities are prominent in Alzheimer disease. In this study, 2 mitochondrial markers, cytochrome oxidase-1 and lipoic acid, a sulfur-containing cofactor required for the activity of several mitochondrial enzyme complexes, were compared using light and electron microscopic analyses and immunoblot assays. Both lipoic acid and cytochrome oxidase-1 immunoreactivity are increased in the cytoplasm of pyramidal neurons in Alzheimer disease compared with control cases. Of significance, lipoic acid was found to be strongly associated with granular structures, and ultrastructure analysis showed localization to mitochondria, cytosol, and, importantly, in organelles identified as autophagic vacuoles and lipofuscin in Alzheimer disease but not control cases. Cytochrome oxidase-1 immunoreactivity was limited to mitochondria and cytosol in both Alzheimer and control cases. These data suggest that mitochondria are key targets of increased autophagic degradation in Alzheimer disease. Whether increased autophagocytosis is a consequence of an increased turnover of mitochondria or whether the mitochondria in Alzheimer disease are more susceptible to autophagy remains to be resolved.

We investigated the relationship between balance and cognitive level in a group of 70 women with no definite Alzheimer’s disease or mild cognitive impairment diagnosis and no impairment of daily activity. Static stabilometry and the Montreal Cognitive Assessment (MoCA) test were performed. The antero-posterior sway component was demonstrated to be the best predictor of the MoCA overall score. As visual and proprioceptive components of balance could safely be excluded in our assessments, the vestibular system is to be considered as a putative link between balance and cognitive impairment.

Researchers since the 1990s have predominantly focused on the amyloid hypothesis and the formation of amyloid fibrils as the culprit behind AD when we began working on soluble Abeta (sAbeta). Unexpectedly, this work produced several novel findings. First, we observed that N-terminal truncated peptides are the major components of soluble and insoluble Abeta in AD; secondly, that all sAbeta species belong to the 42 form and the sAbeta x-40 species is virtually absent in AD parenchyma; thirdly, that Abeta42 in the soluble form is non-detectable by immunoblots in plaque-free, normal brains. The later observation that sAbeta 42 species is present in amyloid beta protein precursor (AbetaPP) over-expressing brains of patients with Down syndrome in prenatal and early postnatal development argued that sAbeta is present in brain in abnormal conditions and that its appearance seeds Abeta aggregation and accumulation. Although the sAbeta we described in intact brain tissue appeared to match the soluble Abeta oligomers detected in cell media, which were subsequently shown to be the most toxic form of Abeta, our research has been virtually ignored by the Alzheimer field. It continues nevertheless. Recently we demonstrated that the sAbeta species present in physiologically aging brains are different from those present in brains with sporadic AD as the latter form oligomers more quickly, are more toxic to neurons, and produce more severe membrane damage than the Abeta species associated with normal brain aging. Furthermore, in familial AD, the composition of soluble Abeta appears to dictate distinctive features of the disease phenotype introducing the notion of Abeta strains, a concept well established in prion diseases.

Autopsy studies have indicated brain accumulation of amyloid-β peptides as a common pathogenetic hallmark of amnestic cognitive impairment (aMCI) and overt Alzheimer's disease (AD). The pathogenesis of AD is still debated but recent reports have even designated AD as type III diabetes. This study aims to assess plasma levels of malondialdehyde, pentosidine, and insulin resistance in a group of aMCI patients, AD subjects, and age- and gender-matched controls, to confirm, beyond the accumulation of amyloid-β, the presence of a metabolic disorder, as a causative/contributive factor for AD. Patients were recruited and diagnosed as aMCI (n = 180), AD (n = 84), and age- and gender-matched controls (n = 62) at three different Italian memory clinics. Plasma insulin and glucose, plasma pentosidine and malondialdehyde (MDA), HOMA-IR and QUICKI score for insulin sensitivities indexes were collected at the basal visit. Plasma MDA levels were higher in the aMCI group who converted to AD compared to controls, stable aMCI subjects, and AD subjects (p < 0.01) respectively, while plasma pentosidine was higher compared to controls. The aMCI group showed a significant correlation between HOMA-IR, QUICKI, insulin, and MDA (p < 0.02). aMCI might be considered the early biochemical active disease stage where glycoxidation, hyperinsulinemia, and pro-amyloidogenic status are at the highest rate while overt AD might indicate the glycoxidative cascade dwindling, ending a process possibly started two decades earlier.

Water-soluble amyloid-beta (wsAbeta) is present in cerebral cortex of subjects at risk of Alzheimer's disease (AD) as well as in normal elderly subjects as a mixture of three major amyloid-beta (Abeta) species: 1-42, py3-42 and py11-42. The three wsAbeta species are nondetectable in brains of young people, free of immunohistochemically detectable amyloid plaques. In the brains of Down's syndrome and APP-mutant transgenic mice, wsAbeta appears long time before amyloid deposition, indicating that it represent the first form of Abeta aggregation and accumulation. In normal brain, wsAbeta is bound to apolipoprotein E that favours its degradation by proteases. The composition of wsAbeta, in terms of the ratio between the full-length 1-42 and the py3-42 peptides, correlates with the severity of clinical and pathological phenotype in familial early onset AD. Water-soluble Abeta is the native counterpart of the Abeta small aggregates (soluble oligomers) that show in vitro an early and high neuronal toxicity.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by pure neurofibrillary tau pathology involving mainly basal ganglia and brain stem nuclei. One of the kinases involved in tau phosphorylation is glycogen synthase 3 kinase (GSK3). In mammals GSK3 is present in two isoforms, alpha and beta regulated by phosphorylation: phosphorylation of Ser9 in GSK3beta or Ser21 in GSK3alpha leads to inactivation while phosphorylation of Tyr216 in GSK3beta or Tyr279 in GSK3alpha leads to activation. We analyzed the protein levels of GSK3alpha/beta and of the phosphorylated forms GSK3beta S(9), GSK3beta Y(216), GSK3alpha Y(279) in brain tissues of subjects with PSP. The analysis failed to show significant differences of all GSK3 isoforms in PSP in comparison to age-matched control cases. This negative result argues against the role of GSK3 in the pathogenesis of PSP.

The purpose of this study was to investigate gene expression in Alzheimer's disease (AD), the most common form of senile dementia. We utilized the microarray technology to simultaneously compare the expression profile of 12,000 human genes in cerebral cortex of AD and normal aging. To identify gene expression related to neurodegeneration, beside the presence of amyloid deposition, we used control brains with abundant amyloid plaques, derived from cognitively normal elderly subjects. The microarray analysis indicated that 314 genes were differentially expressed in AD cerebral cortex, with differences greater than 5 folds in 25 genes. RT-PCR performed on a selected group of genes confirmed the increased expression of the interferon-induced protein 3 in AD brain. This protein, which is highly inducible by both type I and type II interferons, was not previously associated with the neurodegenerative disease.

Scavenger receptors recently have been related to Alzheimer's disease, although it is still unclear whether they contribute to the pathogenesis of the disease or reflect an inflammatory response to the deposition of amyloid beta-protein (Abeta). In this study we demonstrate that CD36, a class B scavenger receptor, is highly expressed in the cerebral cortex of Alzheimer's disease patients and cognitively normal aged subjects with diffuse amyloid plaques compared with age-matched amyloid-free control brains. Moreover, in vitro experiments indicated that Abeta is able to induce CD36 expression in neuronal cells after 24 h treatment. The interaction between CD36 and Abeta has been reported to trigger oxidant production by macrophages and microglia. In line with this observation, we found an increased presence of nitrated proteins in brains showing Abeta loads and CD36 overexpression, independent of the occurrence of Alzheimer's disease pathologic features.

A working group supported by the Office of Rare Diseases of the National Institutes of Health formulated neuropathologic criteria for corticobasal degeneration (CBD) that were subsequently validated by an independent group of neuropathologists. The criteria do not require a specific clinical phenotype, since CBD can have diverse clinical presentations, such as progressive asymmetrical rigidity and apraxia, progressive aphasia, or frontal lobe dementia. Cortical atrophy, ballooned neurons, and degeneration of the substantia nigra have been emphasized in previous descriptions and are present in CBD, but the present criteria emphasize tau-immunoreactive lesions in neurons, glia, and cell processes in the neuropathologic diagnosis of CBD. The minimal pathologic features for CBD are cortical and striatal tau-positive neuronal and glial lesions, especially astrocytic plaques and thread-like lesions in both white matter and gray matter, along with neuronal loss in focal cortical regions and in the substantia nigra. The methods required to make this diagnosis include histologic stains to assess neuronal loss, spongiosis and ballooned neurons, and a method to detect tau-positive neuronal and glial lesions. Use of either the Gallyas silver staining method or immunostains with sensitive tau antibodies is acceptable. In cases where ballooned neurons are sparse or difficult to detect, immunostaining for phospho-neurofilament or alpha-B-crystallin may prove helpful. Methods to assess Alzheimer-type pathology and Lewy body pathology are necessary to rule out other causes of dementia and Parkinsonism. Using these criteria provides good differentiation of CBD from other tauopathies, except frontotemporal dementia and Parkinsonism linked to chromosome 17, where additional clinical or molecular genetic information is required to make an accurate diagnosis.

A series of evidences suggests that enhanced susceptibility to programmed cell death (PCD) is a major pathogenetic factor in Alzheimer's disease (AD). We investigated this issue, analyzing amyloid beta-protein (A beta) production in a model of neuronal PCD, induced by staurosporine in a murine neuroblastoma cell line. When PCD was induced, a 280-290% secreted A beta occurred, in spite of a 20% metabolism and an unchanged A betaPP expression. The increased intracellular A beta reactivity largely colocalized with a marker of ER. Inhibition of caspases blocked the cleavage at the C-terminus of beta PP, but only partially rescued A beta overproduction caused by staurosporine treatment. Our findings suggest that PCD fosters the physiological pathways of A beta production characteristic of neuronal cells, and they confirm the theory that unbalance of PCD is a central event in AD pathogenesis. Moreover, our data indicate that still unidentified cellular mechanisms, other than caspases activation, are responsible of the specific alteration of A betaPP processing during PCD.

The aggregation of amyloid-β (Aβ) peptides plays a crucial role in the onset and progression of Alzheimer's disease. Monomeric form of Aβ, indeed, could exert a physiological role. Considering the anti-oligomerization property of all-trans retinoic acid (ATRA), the involvement of monomeric Aβ1–42 in ATRA-induced neuronal differentiation has been investigated. Four-day ATRA treatment increases β-secretase 1 (BACE1) level, Aβ1–42 production, and receptor for advanced glycation end-products (RAGE) expression. RAGE is a well-recognized receptor for Aβ, and the block of both RAGE and Aβ1–42 with specific antibodies strongly impairs neurite formation in ATRA-treated cells. The involvement of Aβ1–42 and RAGE in ATRA-induced morphologic changes has been confirmed treating undifferentiated cells with different molecular assemblies of peptide: 1 μM monomeric, but not oligomeric, Aβ1–42 increases RAGE expression and favors neurite elongation. The block of RAGE completely prevents this effect. Furthermore, our data underline the involvement of the RAGE-dependent adhesion molecule amphoterin-induced gene and open reading frame-1 as downstream effector of both ATRA and Aβ1–42. In conclusion, our findings identify a novel physiological role for monomeric Aβ1–42 and RAGE in neuronal differentiation.

Department of Physiology, East Carolina University,Greenville, NC 27858, USA1. IntroductionOneof thechallengesfacedbyclinicians andpathol-ogistsis dealingwiththevariabilityoftheclinicalsignsandofthepathologicalchangesthatareassociatedwithdiseases. The truism that two patients with the samedisease are never identical poses no serious diagnosticproblems under most circumstances. However, therearediseasesthatpresentconsiderablevariabilityintheirclinical and pathological phenotype, which not onlymakes the diagnosis difficult but also raises the issue ofthe mechanisms that regulate it.While phenotypically Alzheimer disease, amy-otrophic lateral sclerosis and Huntington chorea havebeenconsideredfairlyhomogenousdiseases, priondis-eases include several clinically and pathologically dis-tinct conditions (Table 1) [33]. Until a few years ago,the sporadic form of prion diseases included only theCreutzfeldt-Jakobdisease(CJD)phenotype. Theinher-ited form included familial CJD, fatal familial insom-nia (FFI), and Gerstmann-Straussler-Scheinkerdisease¨(GSS). These three phenotypes are quite different andhave very unique features. In addition, a fourth sub-typeoffamilialpriondiseases associatedwithinsertionmutationshas eithera mixedphenotypewhichincludesfeatures of both CJD and GSS or a pathological phe-notype with no distinctive features. The form acquiredby infection consists of three phenotypes that are alsoquite distinct, namely the iatrogenic CJD, kuru, andthe new variant CJD reported almost exclusively in theUnited Kingdom.A major interest of our group has been the studyof the mechanisms that regulate the phenotypic het-erogeneity. The understanding of these mechanismsmay lead to a classification of prion diseases based onthe causes rather than the effects of this heterogene-ity. Such classification is likely to be more accurateand may result in a wider detection and more precisediagnosis of these diseases.2. Molecular, cell biology and pathology of theprion proteinThematurenormalorcellularprionprotein(PrP

SIN DOCUMENT*The Dementia Study Group is co-ordinated by Sandro Sorbi andincludes: Margherita Alberoni, Milan; Pasquale Alfieri, SommaVesuviana (NA); Serena Amici, Perugia; Daniele Antana, Rome;Ildebrando Appollonio, Monza (MI); Stefano Avanzi,Castelgoffredo (MN); Antonella Bartoli, Pescara; BrunoBergamasco, Turin; Laura Bracco, Florence; Amalia Bruni,Lamezia Terme (CZ); Orso Bugiani, Milan; Paolo Caffarra, Parma;Carlo Caltagirone, Rome; Antonio Carolei, L’Aquila; Anna RosaCasini, Rome; Luciana Ciannella, Benevento; Antonietta Citterio,Pavia; Antonio Daniele, Rome; Graziella D’Achille, Isernia;Giuseppe Del Curatolo, Grosseto; Grazia Dell’Agnello, Pisa;Daniele Durante, Parma; Elisabetta Farina, Milan; Patrizia Ferrero,Turin; Paolo Forleo, Florence; Guido Gainotti, Rome; PaoloGabriele, Cassino (FR); Emanuela Galante, Castelgoffredo (MN);Virgilio Gallai, Perugia; Roberto Gallassi, Bologna; MaddalenaGasparini, Milan; Bernardino Ghetti, Indianapolis (USA); GiorgioGiaccone, Milan; Floriano Girotti, Milan; Luigi Grimaldi, Milanand Caltanisetta; Serenella Grioli, Catania; Bianca MariaGuarnieri, Pescara; Stefano Grottoli, Fossombrone (PS); FrancescoIemolo, Ragusa; Stefania Latorraca, Florence; Francesco Le Pira,Catania; Gian Luigi Lenzi, Rome; Sebastiano Lorusso, Rimini;Claudio Mariani, Milan; Gabriella Marcon, Udine; VincenzoMascia, Carbonia (CA); Simonetta Mearelli, L’Aquila; MariaMorante, Senigallia (AN); Michela Morbin, Milan; MassimoMusicco, Segrate (MI); Ettore Nardelli, Verona; Paolo Nichelli,Modena; Alessandro Padovani, Brescia; Marco Paganini, Florence;Roberta Pantieri, Bologna; Pietro Parisen, Vicenza; LucillaParnetti, Perugia; Bruno Passerella, Brindisi; Carla Pettenati, Rho(MI); Silvia Piacentini, Florence; Federico Piccoli, Palermo; CarloPiccolini, Perugia; Gilberto Pizzolato, Padova; LeandroProvinciali, Ancona; Nicola Pugliese, Salerno; Francesco Redi,Arezzo; Rosa Maria Ruggieri, Palermo; Umberto Ruggiero,Naples; Marco Saetta, Siracusa; Rudolf Schoenuber, Bolzano;Maria Caterina Silveri, Rome; Sandro Sorbi, Florence; GiuseppeSorrentino, Naples; Patrizia Sucapane, L’Aquila; Andrea Stracciari,Bologna; Massimo Tabaton, Genova; Fabrizio Tagliavini, Milan;Vito Toso, Vicenza; Francesco Valluzzi, Putignano Noci (BA)S. Sorbi ( )Department of Neurological and Psychiatric SciencesUniversity of FlorenceViale Morgagni 85, I-50131 Florence, Italy

In Down syndrome (DS) brain an early, selective accumulation of amyloid β (Aβ) peptides ending at residue 42 (Aβ42) occurs. Whether this event depends on an altered processing of amyloid beta precursor protein (APP) or on defective clearance is uncertain. To investigate this issue, we measured Aβ species 40 and 42 in plasma from 61 patients with DS, 77 age-matched normal controls, and 55 mentally retarded subjects without chromosomal abnormalities. The Aβ 40 and 42 plasma levels were then correlated with apolipoprotein E (apoE) genotypes in all groups of cases, and with I.Q. and Mini Mental Status Examination values in DS subjects. Both Aβ species were significantly elevated in DS compared to control groups, and the extent of their increase reflects that expected from APP gene overexpression. Plasma levels of Aβ 40 and 42 did not correlate with apoE genotypes in DS and control cases, and with the extent of mental retardation in DS subjects. The results indicate that accumulation and clearance of plasma and cerebral Aβ are regulated by different and independent factors. Am. J. Med. Genet. 95:224–228, 2000. © 2000 Wiley-Liss, Inc.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Although the pathogenesis of AD is unknown, it is widely accepted that AD is caused by extracellular accumulation of a neurotoxic peptide, known as Abeta. Mutations in the beta-amyloid precursor protein (APP), from which Abeta arises by proteolysis, are associated with some forms of familial AD (FAD) and result in increased Abeta production. Two other FAD genes, presenilin-1 and -2, have also been shown to regulate Abeta production; however, studies examining the biological role of these FAD genes suggest an alternative theory for the pathogenesis of AD. In fact, all three genes have been shown to regulate programmed cell death, hinting at the possibility that dysregulation of apoptosis plays a primary role in causing neuronal loss in AD. In an attempt to reconcile these two hypotheses, we investigated APP processing during apoptosis and found that APP is processed by the cell death proteases caspase-6 and -8. APP is cleaved by caspases in the intracellular portion of the protein, in a site distinct from those processed by secretases. Moreover, it represents a general effect of apoptosis, because it occurs during cell death induced by several stimuli both in T cells and in neuronal cells.

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22. This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias. Some of these kindreds have mutations in the tau gene. We report here that PSG-1 has a tau mutation at position +16 of the intron after exon 10. The mutation destabilizes a predicted stem-loop structure and leads to an over-representation of the soluble four-repeat tau isoforms, which assemble into wide, twisted, ribbon-like filaments and ultimately result in abundant neuronal and glial tau pathology. The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau. The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.

Michele Fornaro,1 Michael J McCarthy,2,3 Domenico De Berardis,4 Concetta De Pasquale,1 Massimo Tabaton,5 Matteo Martino,6 Salvatore Colicchio,7 Carlo Ignazio Cattaneo,8 Emanuela D'Angelo,9 Pantaleo Fornaro61Department of Formative Sciences, University of Catania, Catania, Italy; 2Department of Psychiatry, Veteran's Affairs San Diego Healthcare System, 3University of California San Diego, La Jolla, CA, USA; 4Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, "ASL 4", Teramo, Italy; 5Department of Internal Medicine and Medical Specialties, University of Genova, Genoa, Italy; 6Department of Neurosciences, Section of Psychiatry, University of Genova, Genoa, Italy; 7Unit of Sleep Medicine, Department of Neuroscience, Catholic University, Rome, Italy; 8National Health System, "ASL 13", Novara, Italy; 9National Health System, "ASL 3", Genoa, ItalyPurpose: The circadian rhythm hypothesis of bipolar disorder (BD) suggests a role for melatonin in regulating mood, thus extending the interest toward the melatonergic antidepressant agomelatine as well as type I (acute) or II cases of bipolar depression.Patients and methods: Twenty-eight depressed BD-II patients received open label agomelatine (25 mg/bedtime) for 6 consecutive weeks as an adjunct to treatment with lithium or valproate, followed by an optional treatment extension of 30 weeks. Measures included the Hamilton depression scale, Pittsburgh Sleep Quality Index, the Clinical Global Impression Scale–Bipolar Version, Young Mania Rating Scale, and body mass index.Results: Intent to treat analysis results demonstrated that 18 of the 28 subjects (64%) showed medication response after 6 weeks (primary study endpoint), while 24 of the 28 subjects (86%) responded by 36 weeks. When examining primary mood stabilizer treatment, 12 of the 17 (70.6%) valproate and six of the 11 (54.5%) lithium patients responded by the first endpoint. At 36 weeks, 14 valproate treated (82.4%) and 10 lithium treated (90.9%) subjects responded. At 36 weeks, there was a slight yet statistically significant (P = 0.001) reduction in body mass index and Pittsburgh Sleep Quality Index scores compared to respective baseline values, regardless of mood stabilizer/outcome. Treatment related drop-out cases included four patients (14.28%) at week 6 two valproate-treated subjects with pseudo-vertigo and drug-induced hypomania, respectively, and two lithium-treated subjects with insomnia and mania, respectively. Week 36 drop outs were two hypomanic cases, one per group.Conclusion: Agomelatine 25 mg/day was an effective and well-tolerated adjunct to valproate/lithium for acute depression in BD-II, suggesting the need for confirmation by future double blind, controlled clinical trials.Keywords: bipolar disorder type-II, acute bipolar depression, agomelatine, adjunctive treatment

Currently, definite peripheral markers for the in vivo diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are not available. Here, we report the presence of pathological prion protein in the olfactory mucosa of a case with sporadic Creutzfeldt-Jakob disease. Prion protein immunoreactivity was detected in an olfactory biopsy performed 45 days after the disease onset, suggesting that the involvement of olfactory epithelium is an early event in sporadic Creutzfeldt-Jakob disease.

Progressive subcortical gliosis (PSG) is a sporadic and familial dementing disease characterized pathologically by astrogliosis at the cortex-white matter junction, a feature present in some prion diseases. With immunocytochemical and Western blot analyses, we investigated the presence of deposits of the prion protein (PrP) and of the protease-resistant PrP isoform, the hallmarks of prion diseases, in six affected members of two large kindreds with PSG. The coding region of the PrP gene was sequenced and chromosomal linkage determined. We demonstrated "diffuse" PrP plaques in the cerebral cortex of two subjects from one kindred and protease-resistant PrP fragments in four of the five subjects examined. We found no mutation in the coding region of the PrP gene. Moreover, the disease was linked to chromosome 17 and not to chromosome 20, where the PrP gene resides. The familial form of PSG is the first human genetic disease characterized by the presence of protease-resistant PrP that lacks a mutation in the coding region of the PrP gene. The linkage to chromosome 17 suggests that other genes are involved in the PrP metabolism. Whether the protease-resistant PrP plays a primary or secondary role in the pathogenesis of this form of PSG remains to be determined.

Although neuronal RNA oxidation is a prominent and established feature in age-associated neurodegenerative disorders such as Alzheimer disease (AD), oxidative damage to neuronal RNA in aging and in the transitional stages from normal elderly to the onset of AD has not been fully examined. In this study, we used an in situ approach to identify an oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the cerebral cortex of 65 individuals without dementia ranging in age from 0.3 to 86 years. We also examined brain samples from 20 elderly who were evaluated for their premortem clinical dementia rating score and postmortem brain pathological diagnoses to investigate preclinical AD and mild cognitive impairment. Relative density measurements of 8OHG-immunoreactivity revealed a statistically significant increase in neuronal RNA oxidation during aging in the hippocampus and the temporal neocortex. In subjects with mild cognitive impairment but not preclinical AD, neurons of the temporal cortex showed a higher burden of oxidized RNA compared to age-matched controls. These results indicate that although neuronal RNA oxidation fundamentally occurs as an age-associated phenomenon, more prominent RNA damage than in normal aging correlates with the onset of cognitive impairment in the prodromal stage of AD.