Helena Targa Dias Anastacio

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene ( HTT ). While classically considered a disease of grey matter, recent imaging data have revealed presymptomatic abnormalities in white matter (WM) tracts. Here, we report lipid changes in glycerophospholipids and sphingolipids from enriched myelin extracts of three WM tracts (internal capsule (IC), dorsomedial prefrontal cortex (dmPFC), corpus callosum (CC)) of HD and control donors. We found no difference in total lipid concentration between HD and control myelin. However, changes were observed at the lipid class level for the CC and dmPFC, with a reduction in the proportion of Hexosylceramides in HD myelin. When lipids were examined at a species level, there was a shift towards shorter glycerophospholipid fatty acid chain length in HD for all three regions, most notably in phosphatidylethanolamine species. This coincides with previous data showing a reduction in fatty acyl chain lengths in sphingolipid species in the caudate of the same donor cohort and suggests a widespread impact of HD on fatty acid metabolism in the brain.

Familial Alzheimer’s disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca²⁺) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca²⁺ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca²⁺ responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that PSEN1 mutations alter Ca²⁺ and glutamate signaling as an early phenotype of FAD.

Familial Alzheimer’s disease (FAD) can be caused by mutations in PSEN1 that encodes presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD, however it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess early calcium and glutamate phenotypes of FAD by measuring the Ca2+ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA and kainate compared to isogenic control and healthy lines. The data shows that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca2+ responses to glutamate and AMPA, but not NMDA or kainate. Together this suggests that PSEN1 mutations alter Ca2+ and glutamate signaling as an early phenotype of FAD.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to loss of cognitive abilities and ultimately, death. With no cure available, limited treatments mostly focus on symptom management. Identifying early changes in the disease course may provide new therapeutic targets to halt or reverse disease progression. Clinical studies have shown that cortical and hippocampal hyperactivity are a feature shared by patients in the early stages of disease, progressing to hypoactivity during later stages of neurodegeneration. The exact mechanisms causing neuronal excitability changes are not fully characterized; however, animal and cell models have provided insights into some of the factors involved in this phenotype. In this review, we summarize the evidence for neuronal excitability changes over the course of AD onset and progression and the molecular mechanisms underpinning these differences. Specifically, we discuss contributors to aberrant neuronal excitability, including abnormal levels of intracellular Ca²⁺ and glutamate, pathological amyloid β (Aβ) and tau, genetic risk factors, including APOE, and impaired inhibitory interneuron and glial function. In light of recent research indicating hyperexcitability could be a predictive marker of cognitive dysfunction, we further argue that the hyperexcitability phenotype could be leveraged to improve the diagnosis and treatment of AD, and present potential targets for future AD treatment development.

Mutations in presenilin 1 and 2 (PS1 and PS2) cause autosomal dominant familial Alzheimer’s disease (FAD). Ferroptosis has been implicated as a mechanism of neurodegeneration in AD since neocortical iron burden predicts Alzheimer’s disease (AD) progression. We found that loss of the presenilins dramatically sensitizes multiple cell types to ferroptosis, but not apoptosis. FAD causal mutations of presenilins similarly sensitizes cells to ferroptosis. The presenilins promote the expression of GPX4, the selenoprotein checkpoint enzyme that blocks ferroptosis by quenching the membrane propagation of lethal hydroperoxyl radicals. Presenilin γ-secretase activity cleaves Notch-1 to signal LRP8 expression, which then controls GPX4 expression by regulating the supply of selenium into the cell since LRP8 is the uptake receptor for selenoprotein P. Selenium uptake is thus disrupted by presenilin FAD mutations, suppressing GPX4 expression. Therefore, presenilin mutations may promote neurodegeneration by derepressing ferroptosis, which has implications for disease-modifying therapeutics.