Alzheimer’s Disease – Dopamine first

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder that causes a significant disruption of normal brain structure and function. At the cellular level, AD is characterized by a massive neuronal loss that primarily affects the hippocampus and cortex, mainly due to the accumulation of intracellular neurofibrillary tangles and extracellular amyloidal neuritic plaques.


Fig.1 -Schematic representation of AD-related mechanisms (Medicinal Research Reviews · 2013)

The hippocampus is a critical brain structure for memory development and damages in this area are believed to be the primary cause for memory loss in AD patients. However, progressive structural alterations in different brain areas may play a pivotal role in the worsening of memory and cognitive dysfunctions. Consistent with these observations, several alterations in the dopaminergic system have been reported in AD patients, together with reduced levels of dopamine (DA) and its receptors. Moreover, DA is a well-recognized modulator of hippocampal synaptic plasticity and its binding to dopaminergic receptors in the dorsal hippocampus is a major determinant of memory encoding.

A recent study published on Nature Communications (DOI: 10.1038/ncomms14727) highlighted how, in a mouse model of AD, at a stage when no Ab-plaque deposition, hyperphosphorylated tau tangles or any sign of neuronal loss in cortical and hippocampal regions has yet occurred, a specific apoptotic process is taking place in the dopaminergic neuronal population in ventral tegmental area. The loss of dopaminergic neurons is paralleled by a reduced outflow of DA in the hippocampus, thus contributing to the deficits of hippocampus-dependent memory and synaptic plasticity, as well as impairment in reward processing. These symptoms are improved by stimulating the dopaminergic system with the administration of L-DOPA or the reduction of its endogenous degradation.

Although the abovementioned process has been observed in an experimental model of AD, it might provide an interesting explanation to recent evidences in AD patients, indicating that the clinical diagnosis of dementia is associated with early non-cognitive symptoms, such as depression and apathy. Based on that, changings in the mood of AD patients would be not a consequence of this pathology but rather an alarm for an early stage development of AD, confirming the strict correlation between depression and subsequent loss of memory.

This picture is somehow symmetrical to what researchers involved in Parkinson’s disease and although the molecular mechanisms underlying early dopaminergic neuron degeneration in the ventral tegmental area remain to be elucidated, these results suggest DA as an important player to consider in the context of AD.

Blog written by Samuele Maramai

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