Early Stage Alzheimer's Disease Pathology Research Articles

A core proteome profile unites mouse models and patients in Alzheimer disease

Levites etal. demonstrate that mouse models of Alzheimer disease (AD), exhibiting amyloid-beta (Αβ) plaque formation, share Αβ responsome proteins with humans. Their work underscores the value of these models in studying Αβ aggregation, cellular vulnerability, and early-stage AD pathology.

Neural Basis of Long-term Musical Memory in Cognitively Impaired Older Persons.

The objective of this study was to determine whether exposure to long-known music would evoke more extensive activation of brain regions minimally affected by Alzheimer disease (AD) pathology and outside traditional memory networks using a functional magnetic resonance imaging paradigm involving listening to long-known and recently-learned music in older adults with cognitive impairment to provide insight into mechanisms of long-term musical memory preservation in cognitively impaired older persons. Seventeen subjects with a diagnosis of mild AD or mild cognitive impairment were recruited for this study. Subjects were scanned using functional magnetic resonance imaging while they performed a music listening task, which included short clips of personally selected music from the patient's past and newly-composed music heard for the first time 60 minutes before scanning. From this task, we obtained group-level maps comparing brain areas associated with long-known and recently-heard music in all subjects. Exposure to long-known music preferentially activated brain regions including the medial prefrontal cortex, precuneus, anterior insula, basal ganglia, hippocampus, amygdala, and cerebellum relative to recently-heard music. These areas are involved in autobiographical memory and associated emotional responses. In addition, they are minimally affected by early stage AD pathology, thus providing a neural basis for long-known musical memory survival. Long-known music activates a bilateral network of prefrontal, emotional, motor, auditory, and subcortical regions (cerebellum, putamen, limbic structures). This extensive activation, relative to recently-heard music, may offer structural and functional clues as to why long-term musical memory appears to be relatively preserved among cognitively impaired older persons.

Interaction effect of Alzheimer's disease pathology and education, occupation, and socioeconomic status as a proxy for cognitive reserve on cognitive performance: in vivo positron emission tomography study.

Educational attainment, occupation, and socioeconomic status have been regarded as major factors influencing cognitive reserve (CR). This study aimed to investigate the interaction effect of amyloid-β/tau burden and education/occupation/socioeconomic status as a proxy for CR on cognitive performance. We analyzed the datasets of the Alzheimer's Disease Neuroimaging Initiative. We included clinically normal subjects and patients with mild cognitive impairment or Alzheimer's disease who had undergone a florbetapir scan within 1 year of a flortaucipir (AV-1451) scan (n = 127). Partial correlation analysis between the standardized uptake value ratio of florbetapir/AV-1451 and the proxy for CR was performed with the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) score as a covariate. Stepwise multiple linear regression analysis was performed to determine the predictors of ADAS-cog performance based on the interaction between the imaging biomarkers and the proxy for CR. We found a significant positive partial correlation between educational level and tau pathology in Braak stage 1/2 areas, and we observed significantly higher tau accumulation among participants with higher education when ADAS-cog score was used as a covariate. The interaction between tau and education was a good predictor of cognitive function, with higher tau accumulation showing a greater association with higher ADAS-cog score among participants with less education than among those with more education. Our findings indicate the protective effect of education against cognitive dysfunction in early-stage Alzheimer's disease pathology and suggest that education may exert a beneficial effect by reducing the adverse cognitive consequences of tau aggregation.

Increased Expression of TrkB and Capzb2 Accompanies Preserved Cognitive Status in Early Alzheimer Disease Pathology

Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) may influence brain reserve, the ability of the brain to tolerate pathological changes without significant decline in function. Here, we explore whether a specifically vulnerable population of human neurons shows a compensatory response to the neuropathological changes of Alzheimer disease (AD) and whether that response depends on an upregulation of the BDNF pathway. We observed increased neuronal TrkB expression associated with early-stage AD pathology (Braak and Braak stages I-II) in hippocampal CA1 region samples from cognitively intact Framingham Heart Study subjects (n = 5) when compared with cognitively intact individuals with no neurofibrillary tangles (n = 4). Because BDNF/TrkB signaling affects memory formation and retention through modification of the actin cytoskeleton, we examined the expression of actin capping protein β2 (Capzb2), a marker of actin cytoskeleton reorganization. Capzb2 expression was also significantly increased in CA1 hippocampal neurons of cognitively intact subjects with early-stage AD pathology. Our data suggest that increased expression of TrkB and Capzb2 accompanies adequate brain reserve in the initial stages of AD pathology. In subsequent stages of AD, the higher levels of TrkB and Capzb2 expression achieved may not be sufficient to prevent cognitive decline.

Inhibition of Choline Acetyltransferase as a Mechanism for Cholinergic Dysfunction Induced by Amyloid-β Peptide Oligomers

Dysregulated cholinergic signaling is an early hallmark of Alzheimer disease (AD), usually ascribed to degeneration of cholinergic neurons induced by the amyloid-β peptide (Aβ). It is now generally accepted that neuronal dysfunction and memory deficits in the early stages of AD are caused by the neuronal impact of soluble Aβ oligomers (AβOs). AβOs build up in AD brain and specifically attach to excitatory synapses, leading to synapse dysfunction. Here, we have investigated the possibility that AβOs could impact cholinergic signaling. The activity of choline acetyltransferase (ChAT, the enzyme that carries out ACh production) was inhibited by ~50% in cultured cholinergic neurons exposed to low nanomolar concentrations of AβOs. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, lactate dehydrogenase release, and [(3)H]choline uptake assays showed no evidence of neuronal damage or loss of viability that could account for reduced ChAT activity under these conditions. Glutamate receptor antagonists fully blocked ChAT inhibition and oxidative stress induced by AβOs. Antioxidant polyunsaturated fatty acids had similar effects, indicating that oxidative damage may be involved in ChAT inhibition. Treatment with insulin, previously shown to down-regulate neuronal AβO binding sites, fully prevented AβO-induced inhibition of ChAT. Interestingly, we found that AβOs selectively bind to ~50% of cultured cholinergic neurons, suggesting that ChAT is fully inhibited in AβO-targeted neurons. Reduction in ChAT activity instigated by AβOs may thus be a relevant event in early stage AD pathology, preceding the loss of cholinergic neurons commonly observed in AD brains.

Dynein Dysfunction Induces Endocytic Pathology Accompanied by an Increase in Rab GTPases: A POTENTIAL MECHANISM UNDERLYING AGE-DEPENDENT ENDOCYTIC DYSFUNCTION

Growing evidence suggests that endocytic dysfunction is intimately involved in early stage Alzheimer disease pathology, such as the accumulation of beta-amyloid precursor protein in enlarged early endosomes. However, it remains unclear how endocytic dysfunction is induced in an age-dependent manner. Cytoplasmic dynein, a microtubule-based motor protein, interacts with another microtubule-associated protein, dynactin. The resulting dynein-dynactin complex mediates minus end-directed vesicle transport, including endosome trafficking. We have previously shown that the interaction between dynein-dynactin complexes is clearly attenuated in aged monkey brains, suggesting that dynein-mediated transport dysfunction exists in aged brains. Our immunohistochemical analyses revealed that age-dependent endocytic pathology was accompanied by an increase in Rab GTPases in aged monkey brains. Here, we demonstrated that siRNA-induced dynein dysfunction reproduced the endocytic pathology accompanied by increased Rab GTPases seen in aged monkey brains and significantly disrupted exosome release. Moreover, it also resulted in endosomal beta-amyloid precursor protein accumulation characterized by increased beta-site cleavage. These findings suggest that dynein dysfunction may underlie age-dependent endocytic dysfunction via the up-regulation of Rab GTPases. In addition, this vicious circle may worsen endocytic dysfunction, ultimately leading to Alzheimer disease pathology.