Lithium Reports

Lithium Reduces Spatial Memory Impairment and Neurodegeneration

Alzheimer’s disease (AD) is a memory disorder characterized by neurodegeneration, a process that results in the progressive decline of cognitive abilities, along with brain plaque accumulation (amyloid-beta) and alterations in synaptic function. Treatment with lithium has been found to offer neural protection against the insults of amyloid-beta neurotoxicity in vitro. Rosiglitazone, a peroxisome proliferator activated receptor-gamma agonist (see “The Antidiabetes Trigger” in the March 2009 issue), has been shown to reduce amyloid-beta neurotoxic effects, including the inflammatory response of microglia and astrocytes. Both lithium and rosiglitazone activate Wnt signaling, a pathway involving a complex network of proteins that has been shown to be related to AD.

In a new study, a double transgenic mouse model was used to examine, in vivo, the effect of lithium and rosiglitazone on amyloid-beta neurotoxicity.1 The mice were tested for spatial memory, and their brain samples were used for histochemical (relating to the the chemistry of cells and tissues) and biochemical analysis. The authors report that both lithium and rosiglitazone significantly reduced (1) spatial memory impairment induced by amyloid burden; (2) amyloid-beta aggregates and amyloid-beta oligomers; and (3) astrocytic and microglia activation.

Also of benefit, lithium and rosiglitazone prevented changes in presynaptic and postsynaptic marker proteins. Finally, both substances activate Wnt signaling, which may be therapeutically beneficial in itself and thereby reduce various AD neuropathological markers.

Caution: A press release by GlaxoSmithKline in February 2007 noted that there is a increased incidence of fractures of the upper arms, hands, and feet in female diabetics given rosiglitazone. This is not good for either diabetics or those with AD, both of whom are increasingly prone to injury from falls (see page 12).

Lithium Enhances Adult Neurogenesis

Adult neurogenesis occurs in the subgranular zone—a brain region in the dentate gyrus—and subventricular zone—a paired brain structure situated throughout the lateral walls of the lateral ventricles. New subgranular-zone neurons migrate into the granule cell layer of the dentate gyrus (DG) and new subventricular-zone neurons appear to enter the association neocortex and entorhinal cortex besides the olfactory bulb.

Alzheimer’s disease (AD) is characterized by neuron loss in the hippocampus, entorhinal cortex, and association neocortex, which underlie the learning and memory deficits associated with it.

In a new study, the authors hypothesized that if the AD brain can support neurogenesis, strategies to stimulate the neurogenesis process could have therapeutic value.2 The researchers had reviewed the literature on 1) the functional significance of adult-born neurons; 2) the occurrence of endogenous neurogenesis in AD; and 3) strategies to stimulate the adult neurogenesis process. They found that: a) new neurons in the adult DG contribute to memory function; b) new neurons are generated in the subgranular and the subventricular zones of AD brains, but they fail to differentiate into mature neurons in the target regions; and c) numerous strategies (including lithium) can enhance adult neurogenesis and promote maturation of newly generated neurons. Lithium might help to compensate for the loss of neurons and improve the memory function in AD.


  1. Toledo EM, Inestrosa NC. Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer’s disease. Mol Psychiatry. 2009 Jul 21. [Epub ahead of print]
  2. Schaeffer EL, Novaes BA, da Silva ER, Skaf HD, Mendes-Neto AG. Strategies to promote differentiation of newborn neurons into mature functional cells in Alzheimer brain. Prog Neuropsychopharmacol Biol Psychiatry 2009 Jul 9. [Epub ahead of print]

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