Non-benzodiazepine Hypnotics and Police-Reported Motor Vehicle Crash Risk among Older Adults: A Sequential Target Trial Emulation.

Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged drowsiness and delayed reaction times. We estimated the effect of initiating Z-drug treatment on the 12-week risk of MVC in a sequential target trial emulation. After linking New Jersey driver licensing and police-reported MVC data to Medicare claims, we emulated a new target trial each week (July 1, 2007 - October 7, 2017) in which Medicare fee-for-service beneficiaries were classified as Z-drug-treated or untreated at baseline and followed for an MVC. We used inverse probability of treatment and censoring weighted pooled logistic regression models to estimate risk ratios (RR) and risk differences with 95% bootstrap confidence limits (CLs). There were 257,554 person-trials, of which 103,371 were Z-drug-treated and 154,183 untreated, giving rise to 976 and 1,249 MVCs, respectively. The intention-to-treat RR was 1.06 (95%CLs 0.95, 1.16). For the per-protocol estimand, there were 800 MVCs and 1,241 MVCs among treated and untreated person-trials, respectively, suggesting a reduced MVC risk (RR 0.83 [95%CLs 0.74, 0.92]) with sustained Z-drug treatment. Z-drugs should be prescribed to older patients judiciously but not withheld entirely over concerns about MVC risk.

Pyroglutamate Aß cascade as drug target in Alzheimer's disease.

One of the central aims in Alzheimer's disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work very well in preclinical model systems both in vitro and in vivo in AD mouse models. However, the lack of translation into clinical settings in the AD field is a challenging endeavor. Although it is long known that N-terminally truncated and pyroglutamate-modified Abeta (AßpE3) peptides are abundantly present in the brain of AD patients, form stable and soluble low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, their potential as drug target has not been generally accepted in the past. This situation has dramatically changed with the report that passive immunization with donanemab, an AßpE3-specific antibody, cleared aymloid plaques and stabilized cognitive deficits in a group of patients with mild AD in a phase II trial. This review summarizes the current knowledge on the molecular mechanisms of generation of AßpE, its biochemical properties, and the intervention points as a drug target in AD.

Discovery of a novel pseudo ß-hairpin structure of N-truncated amyloid-ß for use as a vaccine against Alzheimer's disease.

One of the hallmarks of Alzheimer's disease (AD) are deposits of amyloid-beta (Aß) protein in amyloid plaques in the brain. The Aß peptide exists in several forms, including full-length Aß1-42 and Aß1-40 - and the N-truncated species, pyroglutamate Aß3-42 and Aß4-42, which appear to play a major role in neurodegeneration. We previously identified a murine antibody (TAP01), which binds specifically to soluble, non-plaque N-truncated Aß species. By solving crystal structures for TAP01 family antibodies bound to pyroglutamate Aß3-14, we identified a novel pseudo ß-hairpin structure in the N-terminal region of Aß and show that this underpins its unique binding properties. We engineered a stabilised cyclic form of Aß1-14 (N-Truncated Amyloid Peptide AntibodieS; the 'TAPAS' vaccine) and showed that this adopts the same 3-dimensional conformation as the native sequence when bound to TAP01. Active immunisation of two mouse models of AD with the TAPAS vaccine led to a striking reduction in amyloid-plaque formation, a rescue of brain glucose metabolism, a stabilisation in neuron loss, and a rescue of memory deficiencies. Treating both models with the humanised version of the TAP01 antibody had similar positive effects. Here we report the discovery of a unique conformational epitope in the N-terminal region of Aß, which offers new routes for active and passive immunisation against AD.

Ablation of the Presynaptic Protein Mover Impairs Learning Performance and Decreases Anxiety Behavior in Mice.

The presynaptic protein Mover/TPRGL/SVAP30 is absent in Drosophila and C. elegans and differentially expressed in synapses in the rodent brain, suggesting that it confers specific functions to subtypes of presynaptic terminals. In order to investigate how the absence of this protein affects behavior and learning, Mover knockout mice (KO) were subjected to a series of established learning tests. To determine possible behavioral and cognitive alterations, male and female 8-week-old KO and C57Bl/6J wildtype (WT) control mice were tested in a battery of memory and anxiety tests. Testing included the cross maze, novel object recognition test (NOR), the Morris water maze (MWM), the elevated plus maze (EPM), and the open field test (OF). Mover KO mice showed impaired recognition memory in the NOR test, and decreased anxiety behavior in the OF and the EPM. Mover KO did not lead to changes in working memory in the cross maze or spatial reference memory in the MWM. However, a detailed analysis of the swimming strategies demonstrated allocentric-specific memory deficits in male KO mice. Our data indicate that Mover appears to control synaptic properties associated with specific forms of memory formation and behavior, suggesting that it has a modulatory role in synaptic transmission.

Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age.

The molecular underpinnings associated with cognitive reserve remain poorly understood. Because animal models fail to fully recapitulate the complexity of human brain aging, postmortem studies from well-designed cohorts are crucial to unmask mechanisms conferring cognitive resistance against cumulative neuropathologies. We tested the hypothesis that functionality of the SNARE protein interactome might be an important resilience factor preserving cognitive abilities in old age. Cognition was assessed annually in participants from the Rush "Memory and Aging Project" (MAP), a community-dwelling cohort representative of the overall aging population. Associations between cognition and postmortem neurochemical data were evaluated in functional assays quantifying various species of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) machinery in samples from the inferior temporal (IT, n = 154) and middle-frontal (MF, n = 174) gyri. Using blue-native gel electrophoresis, we isolated and quantified several types of complexes containing the three SNARE proteins (syntaxin-1, SNAP25, VAMP), as well as the GABAergic/glutamatergic selectively expressed complexins-I/II (CPLX1/2), in brain tissue homogenates and reconstitution assays with recombinant proteins. Multivariate analyses revealed significant associations between IT and MF neurochemical data (SNARE proteins and/or complexes), and multiple age-related neuropathologies, as well as with multiple cognitive domains of MAP participants. Controlling for demographic variables, neuropathologic indices and total synapse density, we found that temporal 150-kDa SNARE species (representative of pan-synaptic functionality) and frontal CPLX1/CPLX2 ratio of 500-kDa heteromeric species (representative of inhibitory/excitatory input functionality) were, among all the immunocharacterized complexes, the strongest predictors of cognitive function nearest death. Interestingly, these two neurochemical variables were associated with different cognitive domains. In addition, linear mixed effect models of global cognitive decline estimated that both 150-kDa SNARE levels and CPLX1/CPLX2 ratio were associated with better cognition and less decline over time. The results are consistent with previous studies reporting that synapse dysfunction (i.e. dysplasticity) may be initiated early, and relatively independent of neuropathology-driven synapse loss. Frontotemporal dysregulation of the GABAergic/glutamatergic stimuli might be a target for future drug development.

Synaptic Alterations in Mouse Models for Alzheimer Disease-A Special Focus on N-Truncated Abeta 4-42.

This commentary reviews the role of the Alzheimer amyloid peptide Aß on basal synaptic transmission, synaptic short-term plasticity, as well as short- and long-term potentiation in transgenic mice, with a special focus on N-terminal truncated Aß4-42. Aß4-42 is highly abundant in the brain of Alzheimer's disease (AD) patients. It demonstrates increased neurotoxicity compared to full length Aß, suggesting an important role in the pathogenesis of AD. Transgenic Tg4-42 mice, a model for sporadic AD, express human Aß4-42 in Cornu Ammonis (CA1) neurons, and develop age-dependent hippocampal neuron loss and neurological deficits. In contrast to other transgenic AD mouse models, the Tg4-42 model exhibits synaptic hyperexcitability, altered synaptic short-term plasticity with no alterations in short- and long-term potentiation. The outcomes of this study are discussed in comparison with controversial results from other AD mouse models.

Diesel engine exhaust accelerates plaque formation in a mouse model of Alzheimer's disease.

BACKGROUND: Increasing evidence from toxicological and epidemiological studies indicates that the central nervous system is an important target for ambient air pollutants. We have investigated whether long-term inhalation exposure to diesel engine exhaust (DEE), a dominant contributor to particulate air pollution in urban environments, can aggravate Alzheimer's Disease (AD)-like effects in female 5X Familial AD (5XFAD) mice and their wild-type female littermates. Following 3 and 13 weeks exposures to diluted DEE (0.95 mg/m3, 6 h/day, 5 days/week) or clean air (controls) behaviour tests were performed and amyloid-ß (Aß) plaque formation, pulmonary histopathology and systemic inflammation were evaluated. RESULTS: In a string suspension task, assessing for grip strength and motor coordination, 13 weeks exposed 5XFAD mice performed significantly less than the 5XFAD controls. Spatial working memory deficits, assessed by Y-maze and X-maze tasks, were not observed in association with the DEE exposures. Brains of the 3 weeks DEE-exposed 5XFAD mice showed significantly higher cortical Aß plaque load and higher whole brain homogenate Aß42 levels than the clean air-exposed 5XFAD littermate controls. After the 13 weeks exposures, with increasing age and progression of the AD-phenotype of the 5XFAD mice, DEE-related differences in amyloid pathology were no longer present. Immunohistochemical evaluation of lungs of the mice revealed no obvious genetic background-related differences in tissue structure, and the DEE exposure did not cause histopathological changes in the mice of both backgrounds. Luminex analysis of plasma cytokines demonstrated absence of sustained systemic inflammation upon DEE exposure. CONCLUSIONS: Inhalation exposure to DEE causes accelerated plaque formation and motor function impairment in 5XFAD transgenic mice. Our study provides further support that the brain is a relevant target for the effects of inhaled DEE and suggests that long-term exposure to this ubiquitous air pollution mixture may promote the development of Alzheimer's disease.

Phosphorylation of the amyloid ß-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity.

Aggregation and toxicity of the amyloid ß-peptide (Aß) are considered as critical events in the initiation and progression of Alzheimer's disease (AD). Recent evidence indicated that soluble oligomeric Aß assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the Aß sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization of oligomers of the wild-type Aß remain unclear. Here, we identified an Aß variant phosphorylated at Ser26 residue (pSer26Aß) in transgenic mouse models of AD and in human brain that shows contrasting spatio-temporal distribution as compared to non-phosphorylated Aß (npAß) or other modified Aß species. pSer26Aß is particularly abundant in intraneuronal deposits at very early stages of AD, but much less in extracellular plaques. pSer26Aß assembles into a specific oligomeric form that does not proceed further into larger fibrillar aggregates, and accumulates in characteristic intracellular compartments of granulovacuolar degeneration together with TDP-43 and phosphorylated tau. Importantly, pSer26Aß oligomers exert increased toxicity in human neurons as compared to other known Aß species. Thus, pSer26Aß could represent a critical species in the neurodegeneration during AD pathogenesis.

Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N­truncated Abeta in sporadic Alzheimer disease cases and mouse models.

Solanezumab and Crenezumab are two humanized antibodies targeting Amyloid-ß (Aß) which are currently tested in multiple clinical trials for the prevention of Alzheimer's disease. However, there is a scientific discussion ongoing about the target engagement of these antibodies. Here, we report the immunohistochemical staining profiles of biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab in human formalin-fixed, paraffin-embedded tissue and human fresh frozen tissue. Furthermore, we performed a direct comparative immunohistochemistry analysis of the biosimilar versions of the humanized antibodies in different mouse models including 5XFAD, Tg4-42, TBA42, APP/PS1KI, 3xTg. The staining pattern with these humanized antibodies revealed a surprisingly similar profile. All three antibodies detected plaques, cerebral amyloid angiopathy and intraneuronal Aß in a similar fashion. Remarkably, Solanezumab showed a strong binding affinity to plaques. We also reaffirmed that Bapineuzumab does not recognize N-truncated or modified Aß, while Solanezumab and Crenezumab do detect N-terminally modified Aß peptides Aß4-42 and pyroglutamate Aß3-42. In addition, we compared the results with the staining pattern of the mouse NT4X antibody that recognizes specifically Aß4-42 and pyroglutamate Aß3-42, but not full-length Aß1-42. In contrast to the biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab, the murine NT4X antibody shows a unique target engagement. NT4X does barely cross-react with amyloid plaques in human tissue. It does, however, detect cerebral amyloid angiopathy in human tissue. In Alzheimer mouse models, NT4X detects intraneuronal Aß and plaques comparable to the humanized antibodies. In conclusion, the biosimilar antibodies Solanezumab, Crenezumab and Bapineuzumab strongly react with amyloid plaques, which are in contrast to the NT4X antibody that hardly recognizes plaques in human tissue. Therefore, NT4X is the first of a new class of therapeutic antibodies.

Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer's disease.

Although N-truncated Aß variants are known to be the main constituent of amyloid plaques in the brains of patients with Alzheimer's disease, their potential as targets for pharmacological intervention has only recently been investigated. In the last few years, the Alzheimer field has experienced a paradigm shift with the ever increasing understanding that targeting amyloid plaques has not led to a successful immunotherapy. On the other hand, there can be no doubt that the amyloid cascade hypothesis is central to the etiology of Alzheimer's disease, raising the question as to why it is apparently failing to translate into the clinic. In this review, we aim to refocus the amyloid hypothesis integrating N-truncated Aß peptides based on mounting evidence that they may represent better targets than full-length Aß. In addition to Aß peptides starting with an Asp at position 1, a variety of different N-truncated Aß peptides have been identified starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10 and pyroglutamylated Glu-11. Certain forms of N-truncated species are better correlates for early pathological changes found pre-symptomatically more often than others. There is also evidence that, together with full-length Aß, they might be physiologically detectable and are naturally secreted by neurons. Others are known to form soluble aggregates, which have neurotoxic properties in transgenic mouse models. It has been clearly demonstrated by several groups that some N-truncated Aßs dominate full-length Aß in the brains of Alzheimer's patients. We try to address which of the N-truncated variants may be promising therapeutic targets and which enzymes might be involved in the generation of these peptides.

Changes in the burden of medications that may impair driving among older adults before and after a motor vehicle crash.

BACKGROUND: Medications are one of the most easily modifiable risk factors for motor vehicle crashes (MVCs) among older adults, yet limited information exists on how the use of potentially driver-impairing (PDI) medications changes following an MVC. Therefore, we examined the number and types of PDI medication classes dispensed before and after an MVC. METHODS: This observational study included Medicare fee-for-service beneficiaries aged ≥67 years who were involved in a police-reported MVC in New Jersey as a driver between 2008 and 2017. Analyses were conducted at the "person-crash" level because participants could be involved in more than one MVC. We examined the use of 36 PDI medication classes in the 120 days before and 120 days after MVC. We described the number and prevalence of PDI medication classes in the pre-MVC and post-MVC periods as well as the most common PDI medication classes started and stopped following the MVC. RESULTS: Among 124,954 person-crashes, the mean (SD) age was 76.0 (6.5) years, 51.3% were female, and 83.9% were non-Hispanic White. The median (Q1 , Q3 ) number of PDI medication classes was 2 (1, 4) in both the pre-MVC and post-MVC periods. Overall, 20.3% had a net increase, 15.9% had a net decrease, and 63.8% had no net change in the number of PDI medication classes after MVC. Opioids, antihistamines, and thiazide diuretics were the top PDI medication classes stopped following MVC, at incidences of 6.2%, 2.1%, and 1.7%, respectively. The top medication classes started were opioids (8.3%), skeletal muscle relaxants (2.2%), and benzodiazepines (2.1%). CONCLUSIONS: A majority of crash-involved older adults were exposed to multiple PDI medications before and after MVC. A greater proportion of person-crashes were associated with an increased rather than decreased number of PDI medications. The reasons why clinicians refrain from stopping PDI medications following an MVC remain to be elucidated.

Changes in Physical Function and Physical Therapy Use in Older Veterans Not Infected by CoVID-19 Residing in Community Living Centers During the CoVID-19 Pandemic.

OBJECTIVES: Examine physical function change and physical therapy (PT) use in short-stay and long-stay residents not infected by CoVID-19 within Veterans Affairs (VA) Community Living Centers (CLCs). DESIGN: Retrospective cohort study using Minimum Data Set (MDS) 3.0 assessments. SETTINGS AND PARTICIPANTS: 12,606 Veterans in 133 VA CLCs between September 2019 and September 2020. METHODS: Difference in physical function [MDS Activities of Daily Living Score (MDS-ADL)] and PT use (minutes in past 7 days) from admission to last assessment in a period were compared between the pre-CoVID-19 (September 2019 to February 2020) and early CoVID-19 (April 2020 to September 2020) period using mixed effects regression with multivariable adjustment. Assessments after a positive CoVID-19 test were excluded. Differences were examined in the sample and repeated after stratifying into short- and long-stay stratums. RESULTS: Veterans admitted during early CoVID-19 had more comorbidities, worse MDS-ADL scores, and were more often long-stay residents compared with those admitted during pre-CoVID-19. In comparison to pre-CoVID-19, Veterans in VA CLCs during early CoVID-19 experienced greater improvements in their MDS-ADL (-0.49 points, 95% CI -0.27, -0.71) and received similar minutes of therapy (2.6 minutes, 95% CI -0.8, 6.0). Stratification revealed short-stay residents had relative improvements in their function (-0.69 points, 95% CI -0.44, -0.94) and higher minutes of PT (5.1 minutes, 95% CI 0.9, 9.2) during early CoVID-19 whereas long-stay residents did not see differences in functional change (0.08 points, 95% CI -0.36, 0.51) or PT use (-0.6 minutes, 95% CI -6.1, 4.9). CONCLUSIONS AND IMPLICATIONS: During early CoVID-19, physical function improved while the amount of PT received was maintained compared with pre-CoVID-19 for Veterans in VA CLCs. Short-stay residents experienced greater improvements in physical function and increases in PT use. These findings may be partly due to selection bias relating to Veterans admitted to CLCs during early CoVID-19.

Serious mental illness is associated with elevated risk of hospital readmission in veterans with heart failure.

OBJECTIVE: Adults with serious mental illness (SMI) have high rates of cardiovascular disease, particularly heart failure, which contribute to premature mortality. The aims were to examine 90- and 365-day all-cause medical or surgical hospital readmission in Veterans with SMI discharged from a heart failure hospitalization. The exploratory aim was to evaluate 180-day post-discharge engagement in cardiac rehabilitation, an effective intervention for heart failure. METHODS: This study used administrative data from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services between 2011 and 2019. SMI status and medical comorbidity were assessed in the year prior to hospitalization. Cox proportional hazards models (competing risk of death) were used to evaluate the relationship between SMI status and outcomes. Models were adjusted for VHA hospital site, demographics, and medical characteristics. RESULTS: The sample comprised 189,767 Veterans of which 23,671 (12.5%) had SMI. Compared to those without SMI, Veterans with SMI had significantly higher readmission rates at 90 (16.1% vs. 13.9%) and 365 (42.6% vs. 37.1%) days. After adjustment, risk of readmission remained significant (90 days: HR: 1.07, 95% CI: 1.03, 1.11; 365 days: HR: 1.10, 95% CI: 1.07, 1.12). SMI status was not significantly associated with 180-day cardiac rehabilitation engagement (HR: 0.98, 95% CI: 0.91, 1.07). CONCLUSIONS: Veterans with SMI and heart failure have higher 90- and 365-day hospital readmission rates even after adjustment. There were no differences in cardiac rehabilitation engagement based on SMI status. Future work should consider a broader range of post-discharge interventions to understand contributors to readmission.

Lower odds of successful community discharge after medical hospitalization for Veterans with schizophrenia: A retrospective cohort study of national data.

Medical comorbidity, particularly cardiovascular diseases, contributes to high rates of hospital admission and early mortality in people with schizophrenia. The 30 days following hospital discharge represents a critical period for mitigating adverse outcomes. This study examined the odds of successful community discharge among Veterans with schizophrenia compared to those with major affective disorders and those without serious mental illness (SMI) after a heart failure hospital admission. Data for Veterans hospitalized for heart failure were obtained from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services between 2011 and 2019. Psychiatric diagnoses and medical comorbidities were assessed in the year prior to hospitalization. Successful community discharge was defined as remaining in the community without hospital readmission, death, or hospice for 30 days after hospital discharge. Logistic regression analyses adjusting for relevant factors were used to examine whether individuals with a schizophrenia diagnosis showed lower odds of successful community discharge versus both comparison groups. Out of 309,750 total Veterans in the sample, 7377 (2.4%) had schizophrenia or schizoaffective disorder and 32,472 (10.5%) had major affective disorders (bipolar disorder or recurrent major depressive disorder). Results from adjusted logistic regression analyses demonstrated significantly lower odds of successful community discharge for Veterans with schizophrenia compared to the non-SMI (Odds Ratio [OR]: 0.63; 95% Confidence Interval [CI]: 0.60, 0.66) and major affective disorders (OR: 0.65, 95%; CI: 0.62, 0.69) groups. Intervention efforts should target the transition from hospital to home in the subgroup of Veterans with schizophrenia.

Pyroglutamate amyloid ß (Aß) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.

Pyroglutamate-modified Aß peptides at amino acid position three (Aß(pE3-42)) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). Aß(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated Aß(pE3-42) levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces Aß(pE3-42). TBA42 mice showed age-dependent behavioral deficits and Aß(pE3-42) accumulation. The Aß profile of an established AD mouse model, 5XFAD, was characterized using immunoprecipitation followed by mass spectrometry. Brains from 5XFAD mice demonstrated a heterogeneous mixture of full-length, N-terminal truncated, and modified Aß peptides: Aß(1-42), Aß(1-40), Aß(pE3-40), Aß(pE3-42), Aß(3-42), Aß(4-42), and Aß(5-42). 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6 months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed that Aß(pE3) levels were elevated in FAD42 mice. No change in Aß(x)(-42) or other Aß isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of Aß(pE-42) in FAD42 mice.

Amyloid precursor protein is a biomarker for transformed human pluripotent stem cells.

Increasing evidence suggests an important function of the ß-amyloid precursor protein (APP) in malignant disease in humans; however, the biological basis for this evidence is not well understood at present. To understand the role of APP in transformed pluripotent stem cells, we studied its expression levels in human testicular germ cell tumors using patient tissues, model cell lines, and an established xenograft mouse model. In the present study, we demonstrate the cooperative expression of APP with prominent pluripotency-related genes such as Sox2, NANOG, and POU5F1 (Oct3/4). The closest homologue family member, APLP2, showed no correlation to these stem cell factors. In addition, treatment with histone deacetylase (HDAC) inhibitors suppressed the levels of APP and stem cell markers. Loss of pluripotency, either spontaneously or as a consequence of treatment with an HDAC inhibitor, was accompanied by decreased APP protein levels both in vitro and in vivo. These observations suggest that APP represents a novel and specific biomarker in human transformed pluripotent stem cells that can be selectively modulated by HDAC inhibitors.

Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer's disease.

The progressive accumulation of extracellular amyloid plaques in the brain is a common hallmark of Alzheimer's disease (AD). We recently identified a novel species of Aß phosphorylated at serine residue 8 with increased propensity to form toxic aggregates as compared to non-phosphorylated species. The age-dependent analysis of Aß depositions using novel monoclonal phosphorylation-state specific antibodies revealed that phosphorylated Aß variants accumulate first inside of neurons in a mouse model of AD already at 2 month of age. At higher ages, phosphorylated Aß is also abundantly detected in extracellular plaques. Besides a large overlap in the spatiotemporal deposition of phosphorylated and non-phosphorylated Aß species, fractionized extraction of Aß from brains revealed an increased accumulation of phosphorylated Aß in oligomeric assemblies as compared to non-phosphorylated Aß in vivo. Thus, phosphorylated Aß could represent an important species in the formation and stabilization of neurotoxic aggregates, and might be targeted for AD therapy and diagnosis.

N-truncated amyloid ß (Aß) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits.

N-truncated Aß4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Aß peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aß4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aß4-42 is as toxic as pyroglutamate Aß3-42 and Aß1-42. In line with these findings, treatment of wildtype mice using intraventricular Aß injection induced significant working memory deficits with Aß4-42, pyroglutamate Aß3-42 and Aß1-42. Transgenic mice expressing Aß4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aß4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aß4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction.