Does Lithium Prevent Alzheimerʼs Disease?

Abstract

Lithium salts have a well-established role in the treatment of major affective disorders. More recently, experimental and clinical studies have provided evidence that lithium may also exert neuroprotective effects. In animal and cell culture models, lithium has been shown to increase neuronal viability through a combination of mechanisms that includes the inhibition of apoptosis, regulation of autophagy, increased mitochondrial function, and synthesis of neurotrophic factors. In humans, lithium treatment has been associated with humoral and structural evidence of neuroprotection, such as increased expression of anti-apoptotic genes, inhibition of cellular oxidative stress, synthesis of brain-derived neurotrophic factor (BDNF), cortical thickening, increased grey matter density, and hippocampal enlargement. Recent studies addressing the inhibition of glycogen synthase kinase-3 beta (GSK3B) by lithium have further suggested the modification of biological cascades that pertain to the pathophysiology of Alzheimer's disease (AD). A recent placebo-controlled clinical trial in patients with amnestic mild cognitive impairment (MCI) showed that long-term lithium treatment may actually slow the progression of cognitive and functional deficits, and also attenuate Tau hyperphosphorylation in the MCI-AD continuum. Therefore, lithium treatment may yield disease-modifying effects in AD, both by the specific modification of its pathophysiology via inhibition of overactive GSK3B, and by the unspecific provision of neurotrophic and neuroprotective support. Although the clinical evidence available so far is promising, further experimentation and replication of the evidence in large scale clinical trials is still required to assess the benefit of lithium in the treatment or prevention of cognitive decline in the elderly.

Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer’s disease

“…Importantly, whereas the long-term treatment of elderly patients with low doses of lithium showed to be clinically safe [66], lithium was able to regulate nitric oxide levels in bipolar disorder patients [67]. As the Pla2 activity is significantly reduced in brain tissues [38,60] as well cerebrospinal fluid of patients with AD when compared to controls [42], we investigated whether LiCl would modulate Pla2 mRNA levels and/or enzymatic activity.…”

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

“…However, these putative beneficial effects are still controversial, as demonstrated by several published clinical trials (Fornai et al, 2008a,b; UKMND-LiCALS Study Group et al, 2013). The compound L-690,330, carbamazepine and valproic acid may decrease inositol and inositol triphosphate levels (Sarkar, 2013), thus showing neuroprotective effects in neurodegenerative models (Sarkar, 2005;Fornai et al, 2008a;Feng et al, 2008;Forlenza et al, 2012). Trehalose and resveratrol have shown an important role in reducing protein aggregation and fostering neuronal survival (Gomes et al, 2010;Kim et al, 2007).…”

Reflexiones nerviosas de huecos y de rellenos

“…Y llegado el siglo XXI, y en consonancia con lo que mola en la actualidad, se ha demostrado el efecto neuroprotector del litio a nivel neurocientífico (16) y clí-nico (17). Esta propiedad abre la posibilidad de que el litio pueda tener utilidad en el tratamiento de la enfermedad de Alzheimer (18). Además, el litio inhibe la glucógeno sintasa quinasa 3 (GSK-3, para los amigos), una enzima que se postula implicada en el trastorno bipolar y que también se supone que se dedica a tiempo parcial a enredar en relación con el péptido beta-amiloide y la proteína τ hiperfosforilada, a su vez implicados en la fisiopatología del Alzheimer (19).…”