Critical Time Window of Neuronal Cholesterol Synthesis

The analysis of several conditional mouse mutants targeting neuronal cholesterol synthesis at different ages has revealed a critical time window of neuronal cholesterol synthesis. In the adult brain, astrocytes fully compensate for the loss of cholesterol synthesis in forebrain neurons (Fig. 1).

Fig. 1: While pyramidal neurons in control animals express Squalene synthase (SQS), this signal is lacking in conditional mutants (arrowheads). Astrocytes show increased signal intensity for SQS (asterisk), resulting in an unchanged SQS level in cortex lysates (right panel). In contrast, the level of apolipoprotein E (ApoE), the major apolipoprotein of the CNS that is responsible for cholesterol transport within the brain, is strongly increased.

In contrast, embryonic inactivation leads to severe defects. Conditional mutants are born in Mendelian ratio but die neonatally. Neuronal death is accompanied by microgliosis (Fig. 2). The onset of microgliosis is a few days prior to neuronal degeneration. This observation implies that microglia temporarily support defective neurons. Reduced membrane growth leads to the loss of some neuronal projections. Surprisingly, all developmental defects can be rescued in vitro by cholesterol supplementation. Taken together, neurons can function and mature in the absence of cholesterol synthesis provided sufficient external supply.

Fig. 2: SQS/Nex-cre conditional mutants show massive proliferation and activation of microglia that also upregulated ApoE expression.
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