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.