Biology subjects

Lipponen, A.

Publications and source records attributed to Lipponen, A..

5 recordsLinked to original sources

bioRxiv2024

Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimers disease

Rates of cognitive decline in Alzheimers disease (AD) are extremely heterogeneous, with ages of symptom onset ranging from age 40-100 years and conversion from mild cognitive impairment to AD dementia taking 2-20 years. Development of biomarkers for amyloid-beta (A{beta}) and tau protein aggregates, the hallmark pathologies of AD, have improved patient monitoring/stratification and drug development, but they still only explain 20-40% of the variance in cognitive impairment (CI) in AD. To discover additional molecular drivers and biomarkers of AD dementia, we perform cerebrospinal fluid (CSF) proteomics on 3,416 individuals from six deeply phenotyped prospective AD case-control cohorts. We identify synapse proteins as the strongest correlates of CI, independent of A{beta} and tau. Using machine learning we derive the CSF YWHAG:NPTX2 synapse protein ratio, a robust correlate of CI, which explains 27% of the variance in CI beyond CSF PTau181:A{beta}42, 10% beyond tau PET, and 50% beyond CSF NfL in A{beta} positive individuals. We find YWHAG:NPTX2 also increases with normal aging as early as age 20 and increases at a faster rate in APOE4 carriers and autosomal dominant-AD mutation carriers. Most notably, YWHAG:NPTX2+ individuals (top 25th percentile) are 15-times (HR=15.4 [10.6-22.2]) more likely to experience cognitive decline over 15 years compared to YWHAG:NPTX2- individuals (bottom 25th percentile), and this rises to 19-times (HR=18.9 [10.83-32.9]) with additional stratification by A{beta} and phosphorylated tau status. Lastly, we perform plasma proteomics on 4,245 individuals to develop a plasma-based signature of CI which partly recapitulates CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of A{beta}, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.

neuroscience↗

bioRxiv2024

Estrogen deficiency reduces maximal running capacity and affects serotonin levels differently in the hippocampus and nucleus accumbens in response to acute exercise

ObjectiveEstrogen deficiency is associated with unfavorable changes in body composition and metabolic health. While physical activity ameliorates several of the negative effects, loss of ovarian function is associated with decreased physical activity levels. It has been proposed that the changes in brain neurochemical levels and /or impaired skeletal muscle function may underlie this phenomenon. MethodsWe studied the effect of estrogen deficiency induced via ovariectomy (OVX) in female Wistar rats (n=64). Rats underwent either sham or OVX surgery and were allocated thereafter into four groups matched for body mass and maximal running capacity: sham/control, sham/max, OVX/control, and OVX/max, of which the max groups had maximal running test before euthanasia to induce acute response to exercise. Metabolism, spontaneous activity, and maximal running capacity were measured before (PRE) and after (POST) the surgeries. Three months following the surgery, rats were euthanized, and blood and tissue samples harvested. Proteins were analyzed from gastrocnemius muscle and retroperitoneal adipose tissue via Western blot. Brain neurochemical markers were measured from nucleus accumbens (NA) and hippocampus (HC) using ultra-high performance liquid chromatography. ResultsOVX had lower basal energy expenditure and higher body mass and retroperitoneal adipose tissue mass compared with sham group (p[≤]0.005). OVX reduced maximal running capacity by 17% (p=0.005) with no changes in muscle mass or phosphorylated form of regulatory light chain (pRLC) in gastrocnemius muscle. OVX was associated with lower serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) level in the NA compared with sham (p=0.007). In response to acute exercise, OVX was associated with low serotonin level in the HC and high level in the NA (p[≤]0.024). ConclusionsOur results highlight that OVX reduces maximal running capacity and affects the response of brain neurochemical levels to acute exercise in a brain region-specific manner. These results may offer mechanistic insight into why OVX reduces willingness to exercise.

molecular biology↗

bioRxiv2019

Reduced firing rates of pyramidal cells in frontal cortex of APP/PS1 can be restored by acute treatment with levetiracetam

In recent years aberrant neural oscillations in various cortical areas have emerged as a common physiological hallmark across mouse models of amyloid pathology and patients with Alzheimers disease. However, much less is known about the underlying effect of amyloid pathology on single cell activity. Here, we used high density silicon probe recordings from frontal cortex area of 9 months old APP/PS1 mice to show that resting state Local Field Potential (LFP) power in the theta and beta band is increased in transgenic animals, while single cell firing rates, specifically of putative pyramidal cells, are significantly reduced. At the same time, these sparsely firing pyramidal cells phase-lock their spiking activity more strongly to the ongoing theta and beta rhythms. Furthermore, we demonstrated that the anti-epileptic drug, levetiracetam, can restore principal cell firing rates back to control levels. Overall, our results highlight reduced firing rates of cortical pyramidal cells as a symptom of amyloid pathology and indicate that lifting cortical inhibition might contribute to the beneficial effects of levetiracetam on AD patients.\n\nO_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗

bioRxiv2018

Auditory evoked potentials to changes in speech sound duration in anesthetized mice

Electrophysiological response termed mismatch negativity (MMN) indexes auditory change detection in humans. An analogous response, called the mismatch response (MMR), is also elicited in animals. Mismatch response has been widely utilized in investigations of change detection in human speech sounds in rats and guinea pigs, but not in mice. Since e.g. transgenic mouse models provide important advantages for further studies, we studied processing of speech sounds in anesthetized mice. Auditory evoked potentials were recorded from the dura above the auditory cortex to changes in duration of a human speech sound /a/. In oddball stimulus condition, the MMR was elicited at 53-259 ms latency in response to the changes. The MMR was found to the large (from 200 ms to 110 ms) but not to smaller (from 200 ms to 120-180 ms) changes in duration. The results suggest that mice can represent human speech sounds in order to detect changes in their duration. The findings can be utilized in future investigations applying mouse models for speech perception.

neuroscience↗

bioRxiv2018

Theta and gamma oscillations in the rat hippocampus during attentive lever pressing

The hippocampus is known to be pivotal for spatial memory but emerging evidence suggests its contribution to temporal memories as well. However, it is not clear how the hippocampus represents time and how it synchronizes spatial and temporal presentations into a coherent memory. We assessed the specific role of hippocampal theta and gamma oscillations and their interaction in short-term timing of motor reactions. Rats were trained to maintain lever pressing for 2.5 s and then to quickly release the lever and retrieve water reward from a nearby water port guided by a cue light. In essence, this task allows observation of hippocampal rhythms during timed anticipation when no overt movements take place. Then we implanted wire electrodes to five hippocampal layers for recording local field potentials during the task. Consistent with earlier reports, theta showed a declining trend during the lever press. We also found that fast-gamma declined in tandem with theta while slow-gamma showed an opposite trend. Theta-phase to gamma-amplitude cross-frequency coupling measured with modulation index (MI) varied significantly between the three task phases. Interestingly, also changes in MI were opposite for fast- and slow-gamma. The MI was also related to the task performance, so that during omission trials the MI for fast-gamma in CA1 was smaller than during trials with premature lever release. In addition, the MI in dentate hilus was higher during all error trials than during correctly performed trials. Collectively, these data suggest an important role of synchronization of hippocampal theta and gamma rhythms to timing of cued motor reactions.

neuroscience↗