10 research outputs found
Alzheimer Ć-amyloid peptides normal and abnormal localization
Alzheimer's disease (AD) neuropathology is
characterized by accumulation of āsenileā plaques (SPs)
and neurofibrillary tangles (NFTs) in vulnerable brain
regions. SPs are principally composed of aggregates of
up to 42/43 amino acid Ć-amyloid (AĆ) peptides. The
discovery of familial AD (FAD) mutations in the genes
for the amyloid precursor protein (APP) and presenilins
(PSs), all of which increase AĆ42 production, support
the view that AĆ is centrally involved in the
pathogenesis of AD. AĆ42 aggregates readily, and is
thought to seed the formation of fibrils, which then act
as templates for plaque formation. AĆ is generated by
the sequential intracellular cleavage of APP by Ćsecretase
to generate the N-terminal end of AĆ, and
intramembranous cleavage by g-secretase to generate the
C-terminal end. Cell biological studies have
demonstrated that AĆ is generated in the ER, Golgi, and
endosomal/lysosomal system. A central question
involving the role of AĆ in AD concerns how AĆ causes
disease and whether it is extracellular AĆ deposition
and/or intracellular AĆ accumulation that initiates the
disease process. The most prevalent view is that SPs are
composed of extracellular deposits of secreted AĆ and
that AĆ causes toxicity to surrounding neurons as
extracellular SP. The recent emphasis on the intracellular
biology of APP and AĆ has led some investigators to
consider the possibility that intraneuronal AĆ may
directly cause toxicity. In this review we will outline
current knowledge of the localization of both
intracellular and extracellular AĆ
Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimerās disease-transgenic mice
Alzheimerās disease (AD) is the most common neurodegenerative disease. Most cases of AD are considered idiopathic and likely due to a combination of genetic, environmental, and lifestyle-related risk factors. Despite occurring decades before the typical age of an AD diagnosis, early-life stress (ELS) has been suggested to have long-lasting effects that may contribute to AD risk and pathogenesis. Still, the mechanisms that underlie the role of ELS on AD risk remain largely unknown. Here, we used 5xFAD transgenic mice to study relatively short-term alterations related to ELS in an AD-like susceptible mouse model at 6 weeks of age. To model ELS, we separated pups from their dams for 3Ā h per day from postnatal day 2ā14. Around 6 weeks of age, we found that maternally separated (MS) 5xFAD mice, particularly female mice, displayed increased amyloid-Ī²-immunoreactivity in the anterior cingulate cortex (ACC) and basolateral amygdala (BLA). In anterior cingulate cortex, we also noted significantly increased intraneuronal amyloid-Ī²-immunoreactivity associated with MS but only in female mice. Moreover, IBA1-positive DAPI density was significantly increased in relation to MS in ACC and BLA, and microglia in BLA of MS mice had significantly different morphology compared to microglia in non-MS 5xFAD mice. Cytokine analysis showed that male MS mice, specifically, had increased levels of neuroinflammatory markers CXCL1 and IL-10 in hippocampal extracts compared to non-MS counterparts. Additionally, hippocampal extracts from both male and female MS 5xFAD mice had decreased levels of synapse- and activity-related markers Bdnf, 5htr6, Cox2, and Syp in hippocampus. Lastly, we performed behavioral tests to evaluate anxiety- and depressive-like behavior and working memory but could not detect any significant differences between groups. Overall, we detected several sex-specific molecular and cellular alterations in 6-week-old adolescent 5xFAD mice associated with MS that may help explain the connection between ELS and AD risk