Biology subjects

Andreasson, K. I.

Publications and source records attributed to Andreasson, K. I..

4 recordsLinked to original sources

bioRxiv2025

Synergistic effects of APOE ϵ4 and Alzheimer's pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults

Amyloid-{beta} (A{beta}) and tau pathology begin accumulating decades before clinical symptoms and are influenced by APOE {varepsilon}4, a key genetic risk factor for Alzheimers disease (AD). Although the presence of A{beta}, tau, and APOE {varepsilon}4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9{+/-}5.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. A{beta} was measured using CSF A{beta}42/A{beta}40 or Florbetaben-PET imaging and tau was measured using CSF pTau181. Hippocampal univariate activity and cortical reinstatement - that is, reinstatement of patterns of neocortical activity that were present during memory encoding - were measured during successful memory retrieval. Analyses revealed that APOE {varepsilon}4 was independently associated with greater A{beta} and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by APOE {varepsilon}4. Among APOE {varepsilon}4 non-carriers, A{beta} burden was linked to a pattern of hippocampal hyperactivity. Among APOE {varepsilon}4 carriers, CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of APOE {varepsilon}4 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD. Significance StatementHippocampus-dependent cortical reinstatement is a critical mechanism supporting episodic remembering that contributes to individual differences in memory performance in older adults. However, the contribution of early Alzheimers disease (AD) pathology to variability in this mechanism is unknown. We demonstrate that associations of AD biomarkers with hippocampal activity and cortical reinstatement are moderated by APOE {varepsilon}4 in cognitively unimpaired older adults. Amyloid-{beta}-related hyperactivity was observed in the hippocampus among APOE {varepsilon}4 non-carriers, while CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among APOE {varepsilon}4 carriers. Our findings highlight synergistic effects of APOE and AD pathology on brain function and identify candidate mechanisms that may underlie increased risk of memory impairment in preclinical AD.

neuroscience↗

bioRxiv2024

Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer Disease (AD), and recent proteomic studies highlight a disruption of glial carbohydrate metabolism with disease progression. Here, we report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN) in the first step of the kynurenine pathway, rescues hippocampal memory function and plasticity in preclinical models of amyloid and tau pathology by restoring astrocytic metabolic support of neurons. Activation of IDO1 in astrocytes by amyloid-beta42 and tau oligomers, two major pathological effectors in AD, increases KYN and suppresses glycolysis in an AhR-dependent manner. Conversely, pharmacological IDO1 inhibition restores glycolysis and lactate production. In amyloid-producing APPSwe-PS1{Delta}E9 and 5XFAD mice and in tau-producing P301S mice, IDO1 inhibition restores spatial memory and improves hippocampal glucose metabolism by metabolomic and MALDI-MS analyses. IDO1 blockade also rescues hippocampal long-term potentiation (LTP) in a monocarboxylate transporter (MCT)-dependent manner, suggesting that IDO1 activity disrupts astrocytic metabolic support of neurons. Indeed, in vitro mass-labeling of human astrocytes demonstrates that IDO1 regulates astrocyte generation of lactate that is then taken up by human neurons. In co-cultures of astrocytes and neurons derived from AD subjects, deficient astrocyte lactate transfer to neurons was corrected by IDO1 inhibition, resulting in improved neuronal glucose metabolism. Thus, IDO1 activity disrupts astrocytic metabolic support of neurons across both amyloid and tau pathologies and in a model of AD iPSC-derived neurons. These findings also suggest that IDO1 inhibitors developed for adjunctive therapy in cancer could be repurposed for treatment of amyloid- and tau-mediated neurodegenerative diseases.

neuroscience↗

bioRxiv2024

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease models

Human genetics implicate defective myeloid responses in the development of late onset, age-associated Alzheimers disease (AD). Aging is characterized by a decline in myeloid metabolism that triggers maladaptive, neurotoxic immune responses. TREM1 is an amplifier of pro-inflammatory myeloid responses, and here we find that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation, and hippocampal memory function. Trem1 deficiency rescues age-associated declines in ribose-5P, a glycolytic intermediate and the precursor for purine, pyrimidine, and NAD+ biosynthesis. In vitro, Trem1 deficient microglia are resistant to bioenergetic changes induced by amyloid-{beta}42 oligomers (A{beta}42), suggesting that A{beta}42 stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD model of amyloid accumulation, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy independent of amyloid accumulation or changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency restores synaptic mitochondrial function and cerebral glucose uptake and prevents hippocampal memory decline. In post-mortem human brain, microglial TREM1 expression increases with clinical and neuropathological severity. Thus, TREM1-mediated disruption of myeloid metabolism, both in the periphery and brain, promotes cognitive decline in aging and amyloid accumulation, two major risk factors for AD development.

neuroscience↗

bioRxiv2019

CSF sTREM2 correlates with CSF tau in advancing Parkinson’s disease

Parkinsons disease (PD) is the second most common neurodegenerative disease after Alzheimers disease (AD) and affects 1% of the population above 60 years old. Although PD commonly manifests with motor symptoms, a majority of patients with PD subsequently develop cognitive impairment which often progresses to dementia, a major cause of morbidity and disability. PD is characterized by -synuclein accumulation that frequently associates with amyloid beta (A{beta}) and tau fibrils, the hallmarks of AD neuropathologic changes; this co-occurrence suggests that onset of cognitive decline in PD may be associated with appearance of pathologic A{beta} and/or tau. Recent studies have highlighted the appearance of the soluble form of the Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) receptor in CSF during development of AD. Given the known association of microglial activation with advancing PD, we investigated whether CSF and/or plasma sTREM2 increased with progression to PD dementia. We examined 165 participants consisting of 17 cognitively normal elderly, 45 PD patients with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF A{beta} and tau levels revealed that CSF sTREM2 concentrations were elevated in PD subgroups with abnormal tau, but not A{beta}, CSF concentration. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in PD that is associated with cognitive decline.\n\nOne sentence summaryCSF sTREM2 correlates with CSF tau in PD

neuroscience↗