An Open-Label, Pilot Study of Daratumumab SC in Mild to Moderate Alzheimer's Disease.

We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer's disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and cognitive assessments were performed at baseline, day 176, and day 246. Daratumumab significantly reduced CD38 + CD8 + CD4- T cells after 24 weeks and this effect persisted 11 weeks thereafter. There was no hematological toxicity or unexpected adverse events. Responder analysis showed no improvement on cognitive outcome measures.

18 F-FDG Brain PET/MRI in Amyotrophic Lateral Sclerosis- Frontotemporal Spectrum Disorder (ALS-FTSD).

Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disorder involving both upper and lower motor neurons. Interestingly, 15 to 41% of patients with ALS have concomitant frontotemporal dementia (FTD). Approximately, 50% of patients with ALS can copresent with a broader set of neuropsychological pathologies that do not meet FTD diagnostic criteria. This association resulted in revised and expanded criteria establishing the ALS-frontotemporal spectrum disorder (FTSD). In this case report, we review background information, epidemiology, pathophysiology, and structural and molecular imaging features of ALS-FTSD.

Aß43 levels determine the onset of pathological amyloid deposition.

About 2% of Alzheimer's disease (AD) cases have early onset (FAD) and are caused by mutations in either Presenilins (PSEN1/2) or amyloid-ß precursor protein (APP). PSEN1/2 catalyze production of Aß peptides of different length from APP. Aß peptides are the major components of amyloid plaques, a pathological lesion that characterizes AD. Analysis of mechanisms by which PSEN1/2 and APP mutations affect Aß peptide compositions lead to the implication of the absolute or relative increase in Aß42 in amyloid-ß plaques formation. Here, to elucidate the formation of pathogenic Aß cocktails leading to amyloid pathology, we utilized FAD rat knock-in models carrying the Swedish APP (Apps allele) and the PSEN1 L435F (Psen1LF allele) mutations. To accommodate the differences in the pathogenicity of rodent and human Aß, these rat models are genetically engineered to express human Aß species as both the Swedish mutant allele and the WT rat allele (called Apph) have been humanized in the Aß-coding region. Analysis of the eight possible FAD mutant permutations indicates that the CNS levels of Aß43, rather than absolute or relative increases in Aß42, determine the onset of pathological amyloid deposition in FAD knock-in rats. Notably, Aß43 was found in amyloid plaques in late onset AD and mild cognitive impairment cases, suggesting that the mechanisms initiating amyloid pathology in FAD knock-in rat reflect disease mechanisms driving amyloid pathology in late onset AD. This study helps clarifying the molecular determinants initiating amyloid pathology and supports therapeutic interventions targeting Aß43 in AD.

Semiquantitative Approach to Amyloid Positron Emission Tomography Interpretation in Clinical Practice.

Objective Amyloid positron emission tomography (PET) plays a vital role in the in vivo detection of ß-amyloid accumulation in Alzheimer's disease. Increasingly, trainees and infrequent readers are relying on semiquantitative analyses to support clinical diagnostic efforts. Our objective was to determine if the visual assessment of amyloid PET may be facilitated by relying on semiquantitative analysis. Methods We conducted a retrospective review of [ 18 F]-florbetaben PET/computed tomographies (CTs) from 2016 to 2018. Visual interpretation to determine Aß+ status was conducted by two readers blinded to each other's interpretation. Scans were then post-processed utilizing the MIMneuro software, which generated regional-based semiquantitative Z-scores indicating cortical Aß-burden. Results Of 167 [ 18 F]-florbetaben PET/CTs, 92/167 (reader-1) and 101/167 (reader-2) were positive for amyloid deposition (agreement = 92.2%, κ = 0.84). Additional nine scans were identified as possible Aß-positive based solely on semiquantitative analyses. Largest semiquantitative differences were identified in the left frontal lobe (Z = 7.74 in Aß + ; 0.50 in Aß - ). All unilateral regions showed large statistically significant differences in Aß-burden ( P ≤ 2.08E-28). Semiquantitative scores were highly sensitive to Aß+ status and accurate in their ability to identify amyloid positivity, defined as a positive scan by both readers (AUC ≥ 0.90 [0.79-1.00]). Spread analyses suggested that amyloid deposition was most severe in the left posterior cingulate gyrus. The largest differences between Aß +/Aß- were in the left frontal lobe. Analyses using region-specific cutoffs indicated that the presence of amyloid in the temporal and anterior cingulate cortex, while exhibiting relatively low Z-scores, was most common. Conclusion Visual assessment and semiquantitative analysis provide highly congruent results, thereby enhancing reader confidence and improving scan interpretation. This is particularly relevant, given recent advances in amyloid-targeting disease-modifying therapeutics.

Retrospective review COVID-19 vaccine induced thrombotic thrombocytopenia and cerebral venous thrombosis-what can we learn from the immune response.

INTRODUCTION: Cerebral Venous Thrombosis (CVT), prior to the COVID pandemic, was rare representing 0.5 of all strokes, with the diagnosis made by MRI or CT venography.1-,3 COVID-19 patients compared to general populations have a 30-60 times greater risk of CVT compared to non-affected populations, and up to a third of severe COVID patients may have thrombotic complications.4-8 Currently, vaccines are the best way to prevent severe COVID-19. In February 2021, reports of CVT and Vaccine-induced immune thrombotic thrombocytopenia (VITT) related to adenovirus viral vector vaccines including the Oxford-AstraZeneca vaccine (AZD1222 (ChAdOx1)) and Johnson & Johnson COVID-19 vaccine (JNJ-78436735 (Ad26.COV2·S)), were noted, with a 1/583,000 incidence from Johnson and Johnson vaccine in the United States.11, 12 This study retrospectively analyzed CVT and cross-sectional venography at an Eastern Medical Center from 2018 to 2021, and presents radiographic examples of CVT and what is learned from the immune response. METHODS: After IRB approval, a retrospective review of cross-sectional CTV and MRVs from January 1st 2018 to April 30th 2021, at a single health system was performed. Indications, vaccine status, patient age, sex, and positive finding incidence were specifically assessed during March and April for each year. A multivariable-adjusted trends analysis using Poisson regression estimated venogram frequencies and multivariable logistic regression compared sex, age, indications and vaccination status. RESULTS AND DISCUSSION: From January 1, 2018 to April 30, 2021, (Fig. 1), a total of n = 2206 in patient and emergency room cross-sectional venograms were obtained, with 322 CTVs and 1884 MRVs. In 2018, 2019, 2020, respective totals of cross-sectional venograms were 568, 657, 660, compared to 321 cross-sectional venograms in the first four months of 2021. CTV in 2018, 2019, 2020, respective totals were 51, 86, 97, MRV totals were 517, 571, 563, compared to the 2021 first four month totals of 88 CTVs and 233 MRVs. March, April 2018, 2019, 2020, CTVs respectively were 6, 17, 11, compared to the 2021 first four months of 59 CTVs, comprising 63% of the total 93 CTVs, respective MRVs were 79, 97, 52, compared to 143 MRVs in the first four months of 2021 for 39% of the total 371 MRVs. In March, April 2020 during the pandemic onset, cross-sectional imaging at the East Coast Medical Center decreased, as priorities were on maintaining patient ventilation, high level of care and limiting spread of disease. In March/April 2021, reports of VITT and CVT likely contributed to increased CTVs and MRVs, of 39.65% [1.20-1.63] increase (P < 0.001) from prior. In March, April 2021 of 202 venograms obtained, 158 (78.2.%) were unvaccinated patients, 16 positive for CVT (10.1%), 44 were on vaccinated patients (21.7%), 8 specifically ordered with vaccination as a clinical indication, 2 positive for CVT (4.5%), (odds ratio = 0.52 [0.12-2.38], p = 0.200). CONCLUSION: CTV prior to the COVID pandemic, was rare, responsible for 0.5 of all strokes, at the onset of the pandemic in the East Coast, overall cross-sectional imaging volumes declined due to maintaining ventilation, high levels of care and limiting disease spread, although COVID-19 patients have a 30-60 times greater risk of CVT compared to the general population, and vaccination is currently the best option to mitigate severe disease. In early 2021, reports of adenoviral vector COVID vaccines causing CTV and VITT, led to at 39.65% increase in cross-sectional venography, however, in this study unvaccinated patients in 2021 had higher incidence of CVT (10.1%), compared to the vaccinated patients (4.5%). Clinicians should be aware that VITT CVT may present with a headache 5-30 days post-vaccination with thrombosis best diagnosed on CTV or MRV. If thrombosis is present with thrombocytopenia, platelets <150 × 109, elevated D-Dimer >4000 FEU, and positive anti-PF4 ELISA assay, the diagnosis is definitive.13 VITT CVT resembles spontaneous autoimmune heparin induced thrombocytopenia (HIT), and is postulated to occur from platelet factor 4 (PF4) binding to vaccine adenoviral vectors forming a novel antigen, anti-PF4 memory B-cells and anti-PF4 (VITT) antibodies.14-17.

Significance of Blood and Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: Sensitivity, Specificity and Potential for Clinical Use.

Alzheimer's disease (AD) is the most common type of dementia, affecting more than 5 million Americans, with steadily increasing mortality and incredible socio-economic burden. Not only have therapeutic efforts so far failed to reach significant efficacy, but the real pathogenesis of the disease is still obscure. The current theories are based on pathological findings of amyloid plaques and tau neurofibrillary tangles that accumulate in the brain parenchyma of affected patients. These findings have defined, together with the extensive neurodegeneration, the diagnostic criteria of the disease. The ability to detect changes in the levels of amyloid and tau in cerebrospinal fluid (CSF) first, and more recently in blood, has allowed us to use these biomarkers for the specific in-vivo diagnosis of AD in humans. Furthermore, other pathological elements of AD, such as the loss of neurons, inflammation and metabolic derangement, have translated to the definition of other CSF and blood biomarkers, which are not specific of the disease but, when combined with amyloid and tau, correlate with the progression from mild cognitive impairment to AD dementia, or identify patients who will develop AD pathology. In this review, we discuss the role of current and hypothetical biomarkers of Alzheimer's disease, their specificity, and the caveats of current high-sensitivity platforms for their peripheral detection.

Intramuscular injection of vectorized-scFvMC1 reduces pathological tau in two different tau transgenic models.

With evidence supporting the prion-like spreading of extracellular tau as a mechanism for the initiation and progression of Alzheimer's disease (AD), immunotherapy has emerged as a potential disease-modifying strategy to target tau. Many studies have proven effective to clear pathological tau species in animal models of AD, and several clinical trials using conventional immunotherapy with anti-tau native antibodies are currently active. We have previously generated a vectorized scFv derived from the conformation-dependent anti-tau antibody MC1, scFvMC1, and demonstrated that its intracranial injection was able to prevent tau pathology in adult tau mice. Here, we show that, in a prevention paradigm and in two different tau transgenic models (JNPL3 and P301S), a one-time intramuscular injection of AAV1-scFvMC1 generated a long-lasting peripheral source of anti-tau scFvMC1 and significantly reduced insoluble and soluble tau species in the brain. Moreover, our data showed that scFvMC1 was internalized by the microglia, in the absence of overt inflammation. This study demonstrates the efficacy of intramuscular delivery of vectorized scFv to target tau, and suggests a new potential application to treat AD and the other tauopathies.

Anti-tau conformational scFv MC1 antibody efficiently reduces pathological tau species in adult JNPL3 mice.

Tau, the main component of the neurofibrillary tangles (NFTs), is an attractive target for immunotherapy in Alzheimer's disease (AD) and other tauopathies. MC1/Alz50 are currently the only antibodies targeting a disease-specific conformational modification of tau. Passive immunization experiments using intra-peritoneal injections have previously shown that MC1 is effective at reducing tau pathology in the forebrain of tau transgenic JNPL3 mice. In order to reach a long-term and sustained brain delivery, and avoid multiple injection protocols, we tested the efficacy of the single-chain variable fragment of MC1 (scFv-MC1) to reduce tau pathology in the same animal model, with focus on brain regional differences. ScFv-MC1 was cloned into an AAV delivery system and was directly injected into the hippocampus of adult JNPL3 mice. Specific promoters were employed to selectively target neurons or astrocytes for scFv-MC1 expression. ScFv-MC1 was able to decrease soluble, oligomeric and insoluble tau species, in our model. The effect was evident in the cortex, hippocampus and hindbrain. The astrocytic machinery appeared more efficient than the neuronal, with significant reduction of pathology in areas distant from the site of injection. To our knowledge, this is the first evidence that an anti-tau conformational scFv antibody, delivered directly into the mouse adult brain, is able to reduce pathological tau, providing further insight into the nature of immunotherapy strategies.

Aß1-42-mediated down-regulation of Uch-L1 is dependent on NF-κB activation and impaired BACE1 lysosomal degradation.

Amyloid-ß 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 Aß peptides remains elusive: Aß might not only play a toxic role, but also act as a functional signaling intermediate. We recently reported that Aß1-42 promotes BACE1 transcription through the activation of the JNK-c-jun pathway. Here, we show that the Aß1-42-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, Aß1-42 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 Aß1-42 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.

Amyloid-ß42 activates the expression of BACE1 through the JNK pathway.

The sequential endoproteolytic cleavages operated by the γ-secretase and the ß-secretase (BACE1) on the amyloid-ß protein precursor (AßPP) result in the production of the amyloid-ß (Aß) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of small, soluble aggregates of Aß42 is the major pathogenic event of Alzheimer's disease (AD). However, the physiologic activity of Aß peptides is still elusive. Here, we show that expression of BACE1 is regulated by Aß42, which augments BACE1 gene transcription through the JNK/c-jun signaling pathway. Of note, Aß40 has much less effect on BACE1 expression. These findings unveil a positive feedback loop in which γ-secretase cleavage of AßPP releases a functionally-active peptide, Aß42, that promotes BACE1 transcription. Thus, gene expression induced by Aß42 may have implications in the neuronal dysfunction and degeneration that occurs in AD.

APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant.

An autosomal dominant mutation in the BRI2/ITM2B gene causes familial Danish dementia (FDD). Analysis of FDD(KI) mice, a mouse model of FDD genetically congruous to the human disease since they carry one mutant and one wild-type Bri2/Itm2b allele, has shown that the Danish mutation causes loss of Bri2 protein, synaptic plasticity and memory impairments. BRI2 is a physiological interactor of Aß-precursor protein (APP), a gene associated with Alzheimer disease, which inhibits processing of APP. Here, we show that APP/Bri2 complexes are reduced in synaptic membranes of FDD(KI) mice. Consequently, APP metabolites derived from processing of APP by ß-, α- and γ-secretases are increased in Danish dementia mice. APP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for APP metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that APP and BRI2 functionally interact, and that the neurological effects of the Danish form of BRI2 only occur when sufficient levels of APP are supplied by two alleles. This evidence establishes a pathogenic sameness between familial Danish and Alzheimer's dementias.

Tyr(682) in the intracellular domain of APP regulates amyloidogenic APP processing in vivo.

BACKGROUND: The pathogenesis of Alzheimer's disease is attributed to misfolding of Amyloid-ß (Aß) peptides. Aß is generated during amyloidogenic processing of Aß-precursor protein (APP). Another characteristic of the AD brain is increased phosphorylation of APP amino acid Tyr(682). Tyr(682) is part of the Y(682)ENPTY(687) motif, a docking site for interaction with cytosolic proteins that regulate APP metabolism and signaling. For example, normal Aß generation and secretion are dependent upon Tyr(682) in vitro. However, physiological functions of Tyr(682) are unknown. METHODOLOGY/PRINCIPAL FINDINGS: To this end, we have generated an APP Y682G knock-in (KI) mouse to help dissect the role of APP Tyr(682) in vivo. We have analyzed proteolytic products from both the amyloidogenic and non-amyloidogenic processing of APP and measure a profound shift towards non-amyloidogenic processing in APP KI mice. In addition, we demonstrate the essential nature of amino acid Tyr(682) for the APP/Fe65 interaction in vivo. CONCLUSIONS/SIGNIFICANCE: Together, these observations point to an essential role of APP intracellular domain for normal APP processing and function in vivo, and provide rationale for further studies into physiological functions associated with this important phosphorylation site.

Memory deficits due to familial British dementia BRI2 mutation are caused by loss of BRI2 function rather than amyloidosis.

Familial dementias, which include Alzheimer disease (AD), familial British dementia (FBD), and familial Danish dementia (FDD), are caused by dominantly inherited autosomal mutations and are characterized by the production of amyloidogenic peptides, neurofibrillary tangles (NFTs) and neurodegeneration (St George-Hyslop and Petit, 2005; Garringer et al., 2009). The prevailing pathogenic theory, the "amyloid cascade hypothesis" (Hardy and Selkoe, 2002), posits that the accumulation of amyloidogenic peptides triggers tauopathy, neurodegeneration, and cognitive and behavioral changes. However, this hypothesis is yet to be validated, and causes of dementia may be multifaceted and involve other mechanisms, such as loss of function due to pathogenic mutations. Mouse models of human dementia invariably use transgenic expression systems (LaFerla and Oddo, 2005; McGowan et al., 2006; Vidal et al., 2009; Coomaraswamy et al., 2010) that do not reflect the genotypes of human disease and cannot replicate loss of function. Therefore, we generated a knock-in (KI) mouse model of FBD (FBD(KI)) genetically congruous with the human disease. FBD is caused by a missense mutation at the stop codon of the BRI2 gene (Vidal et al., 1999) and, like FBD patients, FBD(KI) mice carry this mutation in one of the two murine Bri2 alleles. We report that the British mutation drastically reduces expression of mature BRI2 in both KI mice and human FBD brains. This deficit is associated with severe hippocampal memory deficits in FBD(KI) mice. Remarkably, these animals showed no cerebral amyloidosis and tauopathy. Bri2(+/-) mice present memory deficits similar to those in FBD(KI) animals. Collectively, these results indicate that the British BRI2 mutation underlies abnormal memory due to loss of BRI2 function and independently of histopathological alterations typically evident in advanced neurodegenerative disease.

Elevation of {beta}-amyloid 1-42 autoantibodies in the blood of amnestic patients with mild cognitive impairment.

OBJECTIVE: To develop a blood-based test for screening populations at risk for Alzheimer disease. DESIGN: Case-control study. Subjects A total of 180 patients with mild cognitive impairment (MCI) and 105 age-matched, cognitively normal controls. INTERVENTIONS: The titer of beta-amyloid 1-42 autoantibodies in the plasma was obtained at the time of diagnosis and evaluated by enzyme-linked immunosorbent assay before and after dissociation of the antigen-antibody complexes. A total of 107 patients with MCI were followed up for 36 months; 70 of the 107 cases progressed to Alzheimer disease. RESULTS: The average level of beta-amyloid 1-42 plasma autoantibodies in patients with MCI that progressed to Alzheimer disease, but not that of the stable cases, was significantly higher than in cognitively normal controls (P < .001). CONCLUSIONS: The results suggest that the plasma beta-amyloid 1-42 autoantibodies parallel beta-amyloid 42 deposition in the brain, which is known to precede by several years the clinical onset of Alzheimer disease. The evaluation of beta-amyloid 1-42 autoantibodies after dissociation of the complexes is a simple and inexpensive method that can be used to predict the occurrence of Alzheimer disease.

Transgenic expression of the amyloid-beta precursor protein-intracellular domain does not induce Alzheimer's Disease-like traits in vivo.

BACKGROUND: Regulated intramembranous proteolysis of the amyloid-beta precursor protein by the gamma-secretase yields amyloid-beta, which is the major component of the amyloid plaques found in Alzheimer's disease (AD), and the APP intracellular domain (AID). In vitro studies have involved AID in apoptosis and gene transcription. In vivo studies, which utilize transgenic mice expressing AID in the forebrain, only support a role for AID in apoptosis but not gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Here, we have further characterized several lines of AID transgenic mice by crossing them with human Tau-bearing mice, to determine whether over-expression of AID in the forebrain provokes AD-like pathologic features in this background. We have found no evidence that AID overexpression induces AD-like characteristics, such as activation of GSK-3beta, hyperphosphorylation of Tau and formation of neurofibrillary pathology. CONCLUSIONS/SIGNIFICANCE: Overall, these data suggest that AID transgenic mice do not represent a model that reproduces the overt biochemical and anatomo-pathologic lesions observed in AD patients. They can still be a valuable tool to understand the role of AID in enhancing the cell sensitivity to apoptotic stimuli, whose pathways still need to be characterized.

Oxidative stress mediates the pathogenic effect of different Alzheimer's disease risk factors.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting the elderly population. Mechanistically, the major cause of the disease bases on the altered processing of the amyloid-beta (Abeta) precursor protein (APP), resulting in the accumulation and aggregation of neurotoxic forms of Abeta. Abeta derives from the sequential proteolytic cleavage of the beta- and gamma-secretases on APP. The causes of Abeta accumulation in the common sporadic form of AD are not completely known, but they are likely to include oxidative stress (OS). OS and Abeta are linked to each other since Abeta aggregation induces OS in vivo and in vitro, and oxidant agents increase the production of Abeta. Moreover, OS produces several effects that may contribute to synaptic function and cell death in AD. We and others have shown that the expression and activity of beta-secretase (named BACE1; beta-site APP cleaving enzyme) is increased by oxidant agents and by lipid peroxidation product 4-hydroxynonenal and that there is a significant correlation between BACE1 activity and oxidative markers in sporadic AD. OS results from several cellular insults such as aging, hyperglycemia, hypoxic insults that are all well known risk factors for AD development. Thus, our data strengthen the hypothesis that OS is a basic common pathway of Abeta accumulation, common to different AD risk factors.

AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism.

Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-beta (Abeta) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Abeta levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Abeta metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-beta. Direct pharmacological and genetic activation of AMPK lowered extracellular Abeta accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Abeta levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Abeta. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Abeta levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease.

Signaling effect of amyloid-beta(42) on the processing of AbetaPP.

The effects of amyloid-beta are extremely complex. Current work in the field of Alzheimer disease is focusing on discerning the impact between the physiological signaling effects of soluble low molecular weight amyloid-beta species and the more global cellular damage that could derive from highly concentrated and/or aggregated amyloid. Being able to dissect the specific signaling events, to understand how soluble amyloid-beta induces its own production by up-regulating BACE1 expression, could lead to new tools to interrupt the distinctive feedback cycle with potential therapeutic consequences. Here we describe a positive loop that exists between the secretases that are responsible for the generation of the amyloid-beta component of Alzheimer disease. According to our hypothesis, in familial Alzheimer disease, the primary overproduction of amyloid-beta can induce BACE1 transcription and drive a further increase of amyloid-beta precursor protein processing and resultant amyloid-beta production. In sporadic Alzheimer disease, many factors, among them oxidative stress and inflammation, with consequent induction of presenilins and BACE1, would activate a loop and proceed with the generation of amyloid-beta and its signaling role onto BACE1 transcription. This concept of a signaling effect by and feedback on the amyloid-beta precursor protein will likely shed light on how amyloid-beta generation, oxidative stress, and secretase functions are intimately related in sporadic Alzheimer disease.