The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.

SummaryHuman neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during aging are unknown. Here we show that induction of the repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) is a universal feature of normal aging in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Chromatin immunoprecipitation with deep sequencing (ChIP-seq) and expression analysis show that REST represses genes that promote cell death and AD pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein (Aβ) toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional ortholog of REST, C. elegans SPR-4, also protects against oxidative stress and Aβ toxicity. During normal aging, REST is induced in part by cell non-autonomous Wnt signaling. However, in AD, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathologic misfolded proteins. Finally, REST levels during aging are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the aging brain.

The polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. We show here that the serine/threonine kinase LKB1, previously implicated in the establishment of epithelial polarity and control of cell growth, is required for axon specification during neuronal polarization in the mammalian cerebral cortex. LKB1 polarizing activity requires its association with the pseudokinase Stradalpha and phosphorylation by kinases such as PKA and p90RSK, which transduce neurite outgrowth-promoting cues. Once activated, LKB1 phosphorylates and thereby activates SAD-A and SAD-B kinases, which are also required for neuronal polarization in the cerebral cortex. SAD kinases, in turn, phosphorylate effectors such as microtubule-associated proteins that implement polarization. Thus, we provide evidence in vivo and in vitro for a multikinase pathway that links extracellular signals to the intracellular machinery required for axon specification.

Electrical activity in neurons is generally initiated in dendritic processes then propagated along axons to synapses, where it is passed to other neurons. Major structural features of neurons-their dendrites and axons-are thus related to their fundamental functions: the receipt and transmission of information. The acquisition of these distinct properties by dendrites and axons, called polarization, is a critical step in neuronal differentiation. We show here that SAD-A and SAD-B, mammalian orthologs of a kinase needed for presynaptic differentiation in Caenorhabditis elegans, are required for neuronal polarization. These kinases will provide entry points for unraveling signaling mechanisms that polarize neurons.