Cerebral Aβ Pathology Research Articles

Olfactory Dysfunction Is Associated with Cerebral Amyloid Deposition and Cognitive Function in the Trajectory of Alzheimer's Disease.

Olfactory dysfunction is consistently observed in individuals with Alzheimer's disease (AD), but its association with beta-amyloid (Aβ) deposition remains unclear. This study aimed to investigate the relationship among olfactory function, cerebral Aβ deposition, and neuropsychological profiles in individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia. A total of 164 participants were included, and olfactory function was assessed using the brief smell identification test (B-SIT). Cerebral Aβ deposition was measured using [18F]-flutemetamol PET imaging (A-PET). The results show a significant group difference in olfactory function, with the highest impairment observed in the Aβ-positive MCI and AD dementia groups, and the impairment was the lowest in Aβ-negative NCI. Olfactory dysfunction was positively associated with cognitive impairments across multiple domains. Furthermore, individuals with Aβ deposition had lower olfactory function compared to those without Aβ, even within the same neuropsychological stage. The association between olfactory dysfunction and Aβ deposition was observed globally and in specific cortical regions. These findings suggest that olfactory dysfunction is associated with both cognitive function and cerebral Aβ pathology in the trajectory of AD. Olfactory deficits may serve as an additional marker for disease progression and contribute to understanding the underlying mechanisms of AD.

Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the AppNL−F/NL−F knock-in mouse model of Alzheimer’s disease

BackgroundAβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer’s disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD.MethodsCSF, serum, and brain tissue were collected from 3- to 18-month-old AppNL−F/NL−F knock-in mice (n = 48) and 2–18-month-old AppNL/NL knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay.ResultsIn AppNL−F/NL−F knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in AppNL/NL knock-in mice during the observation time.ConclusionsOur findings suggest a temporal sequence of events in AppNL−F/NL−F knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum.

Default mode network dissociation linking cerebral beta amyloid retention and depression in cognitively normal older adults.

Cerebral beta amyloid (Aβ) deposition and late-life depression (LLD) are known to be associated with the trajectory of Alzheimer's disease (AD). However, their neurobiological link is not clear. Previous studies showed aberrant functional connectivity (FC) changes in the default mode network (DMN) in early Aβ deposition and LLD, but its mediating role has not been elucidated. This study was performed to investigate the distinctive association pattern of DMN FC linking LLD and Aβ retention in cognitively normal older adults. A total of 235 cognitively normal older adults with (n = 118) and without depression (n = 117) underwent resting-state functional magnetic resonance imaging and 18F-flutemetamol positron emission tomography to investigate the associations between Aβ burden, depression, and DMN FC. Independent component analysis showed increased anterior DMN FC and decreased posterior DMN FC in the depression group compared with the no depression group. Global cerebral Aβ retention was positively correlated with anterior and negatively correlated with posterior DMN FC. Anterior DMN FC was positively correlated with severity of depression, whereas posterior DMN FC was negatively correlated with cognitive function. In addition, the effects of global cerebral Aβ retention on severity of depression were mediated by subgenual anterior cingulate FC. Our results of anterior and posterior DMN FC dissociation pattern may be pivotal in linking cerebral Aβ pathology and LLD in the course of AD progression. Further longitudinal studies are needed to confirm the causal relationships between cerebral Aβ retention and LLD.

RAB39B is redistributed in dementia with Lewy bodies and is sequestered within aβ plaques and Lewy bodies.

Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X‐linked Parkinson’s disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha‐Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined. Here, analysis of the spatial distribution and expression of RAB39B was conducted in post‐mortem human brain tissue from cases of dementia with Lewy bodies (DLB, n = 10), Alzheimer’s disease (AD, n = 12) and controls (n = 12). Assessment of cortical RAB39B immunoreactivity using tissue microarrays revealed an overall reduction in the area of RAB39B positive gray matter in DLB cases when compared to controls and AD cases. Strikingly, RAB39B co‐localized with beta‐amyloid (Aβ) plaques in all cases examined and was additionally present in a subpopulation of Lewy bodies (LBs) in DLB. Biochemical measures of total RAB39B levels within the temporal cortex were unchanged between DLB, AD and controls. However, upon subcellular fractionation, a reduction of RAB39B in the cytoplasmic pool was found in DLB cases, alongside an increase of phosphorylated aSyn and Aβ in whole tissue lysates. The reduction of cytoplasmic RAB39B is consistent with an impaired reserve capacity for RAB39B‐associated functions, which in turn may facilitate LB aggregation and synaptic impairment. Collectively, our data support the involvement of RAB39B in the pathogenesis of DLB and the co‐aggregation of RAB39B with Aβ in plaques suggests that age‐associated cerebral Aβ pathology may be contributory to the loss of RAB39B. Thus RAB39B, its associated functional pathways and its entrapment in aggregates may be considered as future targets for therapeutic interventions to impede the overall pathological burden and cellular dysfunction in Lewy body diseases.

Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice.

Amyloid plaques in Alzheimer’s disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, highlighting gut–brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular Aβ deposition in the IEB occur before cerebral Aβ aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral Aβ pathology. Lastly, we report Aβ deposition in the intestinal autopsy from AD patients with confirmed cerebral Aβ pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota.

Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota

Alzheimer’s disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer’s disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.

Common Impact of Chronic Kidney Disease and Brain Microhemorrhages on Cerebral Aβ Pathology in SHRSP.

While chronic kidney disease seems to be an independent risk factor for cognitive decline, its impact on cerebral amyloid-β (Aβ) depositions, one hallmark of Alzheimer's Disease (AD) pathology, has not been investigated. Utilizing 80 male nontransgenic spontaneously hypertensive stroke prone rats (SHRSP) at various ages (12 to 44 weeks), tubulointerstitial renal damage, prevalence of cerebral microhemorrhages and Aβ accumulations were quantified. Using age-adjusted general linear models we investigated the main and interaction effects of renal damage and cerebral microhemorrhages on cerebral Aβ load. In addition, using post mortem human brain tissue of 16 stroke patients we examined the co-localization of perivascular Aβ deposits and small vessel wall damage. Statistical models revealed an age-independent main effect of tubulointerstitial kidney damage on brain Aβ accumulations, which was reinforced by the consecutive presence of cerebral microhemorrhages. Moreover, cerebral microhemorrhages independently predicted brain Aβ burden in SHRSP. In up to 69% of all human cases perivascular Aβ deposits were detected in the direct vicinity of small vessel wall damage. Our results support the associations between vascular pathology and Aβ deposition, and demonstrate a relationship between chronic kidney disease and cerebral Aβ pathology. Hence, our data suggest that prevention of chronic renal damage may reduce cerebral Aβ pathology.

Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by extracellular deposits of amyloid β peptide (Aβ) and microglia-dominated neuroinflammation. The therapeutic options for AD are currently limited. In this study, we investigated the antiinflammatory effects and the underlying molecular mechanisms of Ginkgo biloba extract EGb 761 when administered to TgCRND8 AD mice, which overexpress human Alzheimer's amyloid precursor protein (APP) specifically in neurons. We gave APP-transgenic mice EGb 761 as a dietary supplement for 2 or 5months. Plasma concentrations of EGb 761 components in mice were in the same range as such concentrations in humans taking EGb 761 at the recommended dose (240mg daily). Treatment with EGb 761 for 5months significantly improved the cognitive function of the mice as measured by the Barnes Maze test. It also attenuated the loss of synaptic structure proteins, such as PSD-95, Munc18-1, and SNAP25. Treatment with EGb 761 for 5months inhibited microglial inflammatory activation in the brain. The effects of treatment with EGb 761 for 2months were weak and not statistically significant. Moreover, EGb 761 activated autophagy in microglia. Treatment with EGb 761 decreased Aβ-induced microglial secretion of TNF-α and IL-1β and activation of caspase-1, both of which were abolished by the inhibition of autophagy. Treatment with EGb 761 also reduced the concentrations of NLRP3 protein that colocalized with LC3-positive autophagosomes or autolysosomes in microglia. Additionally, long-term treatment with EGb 761 may reduce cerebral Aβ pathology by inhibiting β-secretase activity and Aβ aggregation. Therefore, long-term treatment with G. biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology by antiinflammatory and Aβ-directed mechanisms.