Presenilin/gamma-Secretase and Inflammation

Abstract

Presenilins (PS) are the catalytic components of gamma-secretase, an aspartyl protease that regulates through proteolytic processing the function of multiple signaling proteins. Specially relevant is the gamma-secretase-dependent cleavage of the beta-amyloid precursor protein (APP) since generates the beta-amyloid (Abeta) peptides that aggregate and accumulate in the brain of Alzheimer's disease (AD) patients. Abnormal processing and/or accumulation of Abeta disrupt synaptic and metabolic processes leading to neuron dysfunction and neurodegeneration. Studies in presenilin conditional knockout mice have revealed that presenilin-1 is essential for age-dependent Abeta accumulation and inflammation. By contrast, mutations in the presenilin genes responsible for early onset familial AD cause rapid disease progression and accentuate clinical and pathological features including inflammation. In addition, a number of loss of function mutations in presenilin-1 have been recently associated to non-Alzheimer's dementias including frontotemporal dementia and dementia with Lewy bodies. In agreement, total loss of presenilin function in the brain results in striking neurodegeneration and inflammation, which includes activation of glial cells and induction of proinflammatory genes, besides altered inflammatory responses in the periphery. Interestingly, some non-steroidal anti-inflammatory drugs that slow cognitive decline and reduce the risk of AD, decrease amyloidogenic Abeta42 levels by modulating allosterically PS/gamma-secretase. In this review, I present current evidence supporting a role of presenilin/gamma-secretase signaling on gliogenesis and gliosis in normal and pathological conditions. Understanding the cellular mechanisms regulated by presenilin/gamma-secretase during chronic inflammatory processes may provide new approaches for the development of effective therapeutic strategies for AD.

Keywords: Alzheimer's disease; NSAID; Notch; amyloid; frontotemporal dementia; neurodegeneration; neuroinflammation.

Figure 1

Mechanisms regulating brain inflammation by PS/γ secretase. Schematic model showing signaling mechanisms regulated by PS/γ-secretase on inflammation. The γ-secretase-dependent cleavage of APP generates the Aβ peptide that following oligomerization (Aβ olig) accumulates in plaques in AD brain (dashed lines). Aβ stimulates inflammatory cells that upon activation upregulate proinflammatory genes and secrete inflammatory molecules. Activated microglia and reactive astrocytes accumulate surrounding the amyloid plaques. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce inflammation by acting through different molecular mechanisms including inhibition of COX enzymes in microglia or by reducing Aβ42 generation through γ-secretase or BACE1. On the other hand, the γ-secretase-dependent cleavage of Notch receptor generates the Notch intracellular domain (NICD), which promotes radial glial and astrocyte fates in neural precursor cells (NPC) by affecting target gene expression. By contrast, γ-secretase-dependent cleavage of ErbB4 generates the ErbB4 intracellular domain (EICD) that represses expression of astrocytic genes. In addition, PS downregulate the expression of inflammatory genes in glial cells by still unknown mechanisms.

Figure 2

PS1 inactivation reduces brain inflammation in APP transgenic mice. The images show consecutive serial brain sections of 6 month-old APP (APP_Sw,Ind; J20) and PS1cKO;APP transgenic (Tg) mice stained with antibodies against Aβ42, GFAP and CD45. Reactive astrocytes labeled with a GFAP antibody and activated microglia stained with anti CD45 are found in the hippocampus of APP mice, but not in PS1cKO;APP mice. Activated microglia and astrocytes in APP brains are closely associated with Aβ42-containing plaques as observed in these three consecutive brain sections. Insets: Higher-power views of the lesions marked with arrowheads.