Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype

Abstract

Background: Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer’s disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-β (Aβ), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration. Accumulating evidence suggests that microglia, resident innate immune cells in the central nervous system, play a key role in AD neurodegeneration. Objective: Previous work has identified a regulatory role for PS2 in microglia. We hypothesized that PSEN2 variants lead to dysregulated microglia, which could further contribute to disease acceleration. To mimic the genotype of EOFAD patients, we created a transgenic mouse expressing PSEN2 N141I on a mouse background expressing one wildtype PS2 and two PS1 alleles. Results: Microglial expression of PSEN2 N141I resulted in impaired γ-secretase activity as well as exaggerated inflammatory cytokine release, NFκB activity, and Aβ internalization. In vivo, PS2 N141I mice showed enhanced IL-6 and TREM2 expression in brain as well as reduced branch number and length, an indication of “activated” morphology, in the absence of inflammatory stimuli. LPS intraperitoneal injection resulted in higher inflammatory gene expression in PS2 N141I mouse brain relative to controls. Conclusion: Our findings demonstrate that PSEN2 N141I heterozygosity is associated with disrupted innate immune homeostasis, suggesting EOFAD variants may promote disease progression through non-neuronal cells beyond canonical dysregulated Aβ production.

Alzheimer’s Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation

“…First, PSENs may more meaningfully influence neuropsychiatric symptoms of AD [102]. Second, PSEN2 is a key contributor underlying neuroinflammation [103,104]; loss of normal PSEN2 function disrupts canonical γ-secretase activity to promote a proinflammatory phenotype mediated by microglial activation and cytokine release [104,105]. Microglial activation and cytokine release can also promote the development of epilepsy [106,107].…”

Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus

“…Inherent to this dictum is the need for simultaneous appraisal of immunological changes — innate and adaptive — in peripheral and central compartments over time, and for mapping of these changes onto predictive models of AD pathogenesis and progression. This kind of assessment will require the use of large-scale cohorts of asymptomatic ageing adults in midlife through to late life and of carriers of AD risk alleles (for example, APOE ε4) and causative gene mutations (for example, mutations in PS1 or PS2 ) 135 – 137 before disease onset. This approach will also provide an understanding of whether peripheral immune changes occur in tandem with or precede CNS immune alterations in the development of AD.…”

Chronic Seizures Induce Sex-Specific Cognitive Deficits with Loss of Presenilin 2 Function

“…Microglia derived from PSEN2 KO mice are primed to exhibit enhanced inflammatory cytokine release in response to insult in vitro (Jayadev et al, 2010b), possibly enhancing susceptibility to neurological damage with chronic seizures. Indeed, the most common PSEN2 variant (N141I) worsens inflammatory response of primary microglia (Fung et al, 2020). While our study presently did not address the changes in seizure-induced microglial response, future work is needed to evaluate how chronic seizures influence neuroinflammation in an ADassociated brain.…”

“…This study highlights major sex-specific impacts of uncontrolled chronic seizures on reactive astrogliosis. Considering that the most common PSEN2 variant (N141I) worsens inflammatory response of primary microglia [72], future work is needed to define whether chronic seizures and loss of normal PSEN2 function additively or synergistically modify other neuroinflammatory markers in a sex-specific manner. PSEN2 KO mice aged >6-months-old fill an important gap to define the extent to which chronic seizures and altered neuroinflammatory milieu can ultimately alter cognitive deficits with advanced age, as well as whether such impacts are sex-specific.…”