N-terminally truncated A␤ peptides starting with pyroglutamate (A␤pE3) represent a major fraction of all A␤ peptides in the brain of Alzheimer disease (AD) patients. A␤pE3 has a higher aggregation propensity and stability and shows increased toxicity compared with full-length A␤. In the present work, we generated a novel monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of A␤pE3 and studied the potential involvement of oligomeric A␤pE3 in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost nondetectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal and blood vessel staining was observed. Using a novel sandwich ELISA significantly decreased levels of oligomers in plasma samples from patients with AD compared with healthy controls were identified. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall A␤ plaque load and A␤pE3 levels, and normalized behavioral deficits. These data indicate that 9D5 is a therapeutically and diagnostically effective monoclonal antibody targeting low molecular weight A␤pE3 oligomers. Alzheimer disease (AD)3 represents the most frequent form of dementia and is characterized by the presence of extracellular amyloid plaques composed of amyloid-␤ (A␤) surrounded by dystrophic neurites and neurofibrillary tangles. The discovery that certain early-onset familial forms of AD may be caused by enhanced levels of A␤ peptides have led to the hypothesis that amyloidogenic A␤ is intimately involved in the AD pathogenic process (1). In the past extracellular A␤ has been regarded as the major culprit, whereas more recent evidence now points to toxic effects of A␤ in intracellular compartments (2-3). In addition, other concepts propose that the soluble oligomers and the ␤-sheet containing amyloid fibrils are the toxic forms of A␤ (4 -6). Supporting this notion, it has been demonstrated that soluble oligomeric A␤42, but not plaque-associated A␤, correlates best with cognitive dysfunction in AD (7-8). Oligomers are formed preferentially intracellulary within neuronal processes and synapses rather than extracellularly (9 -10). Besides full-length A␤ peptides starting with an aspartate at position 1, a variety of different N-truncated A␤ peptides have been identified in AD brains. Ragged peptides including phenylalanine at position 4 of A␤ have been reported as early as 1985 by Masters et al. (11). In contrast, no N-terminal sequence could be obtained from cores purified in a sodium dodecyl sulfate-containing buffer, which led to the assumption that the N terminus could be blocked (12-13). The presence of A␤pE3 (N-terminally truncated A␤ starting with pyroglutamate) in AD brain was subsequently shown using mass spectrometry of purified A␤ peptides, explaining at least partially initial difficulties in sequencing A␤ peptides purified from human brain tissue (14). The author...

In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.

Background: Multiple lines of research suggest that increased cystatin C activity in the brain

Cathepsin B is suggested to be involved in amyloid-β (Aβ) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls. Cathepsin B, Cystatin C, Aβ1-40 and Aβ1-42, total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin C), xMAP Luminex technology (Aβ1-40 and Aβ1-42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Plasma cathepsin B levels were higher in persons with AD compared to healthy controls, both in unadjusted models and in multivariable models adjusting for age, gender, APOE genotype, cystatin C, and albumin levels: Odds ratio (OR) for AD per 1 SD of plasma cathepsin B; 2.04, 95% confidence interval (CI); 1.01-4.14, p= 0.05. There was no difference between diagnostic groups in cathepsin B levels in CSF: OR for AD per 1 SD of CSF cathepsin B; 0.93, 95% CI; 0.37-2.30, p= 0.87. Plasma cathepsin B levels were higher in persons with AD compared to healthy controls whereas there was no difference between diagnostic groups in cathepsin B levels in CSF. Further investigation of cathepsin B as a predictor of AD is warranted.

Inflammation is suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Serum interleukin-6 (IL-6) and high sensitivity serum reactive protein C (hsCRP) as markers of systemic inflammation were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 1062 and age 77, n = 749). In addition, serum amyloid protein A (SAA) and urinary prostaglandin F2alpha (PGF2alpha) metabolite levels were analyzed at age 77 in this cohort. Two serial samples (at ages 70 and 77) were available from 704 individuals. Using Cox regression analyses, associations between serum IL-6, hsCRP, SAA and PGF2alpha metabolite levels and risk of AD, any type of dementia (all-cause dementia) and non-AD dementia were analyzed. On follow-up (median, 11.3 years) in the age 70 cohort, 81 subjects developed AD and 165 subjects developed all-cause dementia. Serum IL-6, hsCRP, SAA, or PGF2alpha levels were not associated with risk of AD. At age 70, high IL-6 levels were associated with an increased risk of non-AD dementia (Hazard ratio 2.21 for above vs. below/at median, 95%confidence interval 1.23-3.95, p-value = 0.008). A longitudinal change in CRP or IL-6 levels was not associated with AD ordementia. In conclusion, Serum IL-6, hsCRP, SAA, and PGF2alpha levels are not associated with the risk of AD. High serum IL-6 levels may be associated with increased risk of non-AD dementia.