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Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ)(More)
Accumulation of beta-amyloid (Abeta) peptide and hyperphosphorylation of tau in the brain are pathological hallmarks of Alzheimer's disease (AD). Agents altering these pathological events might modify clinical disease progression. NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) is an octapeptide that has shown neuroprotective effects in various in vitro and in vivo(More)
Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing(More)
Several epidemiological and preclinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower β-amyloid (Aβ) production and inhibit neuroinflammation. However, follow-up clinical trials, mostly using selective cyclooxygenase (COX)-2 inhibitors,(More)
Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early(More)
Accumulation of amyloid beta peptide (Abeta) in brain is a hallmark of Alzheimer's disease (AD). Inhibition of beta-site amyloid precursor protein (APP)-cleaving enzyme-1 (BACE1), the enzyme that initiates Abeta production, and other Abeta-lowering strategies are commonly tested in transgenic mice overexpressing mutant APP. However, sporadic AD cases, which(More)
Fyn kinase phosphorylates tau and exacerbates amyloid beta (Aβ)-mediated synaptic dysfunction. However, Fyn also increases the nonpathological cleavage of amyloid precursor protein (APP), suggesting opposing roles for Fyn in the pathogenesis of Alzheimer's disease (AD). To determine the effect of Fyn on both Aβ and tau pathologies, we crossed homozygous(More)
BACKGROUND Apolipoprotein E (apoE) is postulated to affect brain Abeta levels through multiple mechanisms--by altering amyloid precursor protein (APP) processing, Abeta degradation, and Abeta clearance. We previously showed that an apoE-derived peptide containing a double repeat of the receptor-binding region was similarly effective in increasing APP(More)
Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as the brain ages is an aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and(More)
Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of(More)