Background: Alzheimer's disease (AD) is characterized by accumulation and aggregation of
beta-amyloid peptide, neurofibrillary tangles of hyperphosphorylated tau, neuroinflammation, synaptic
degeneration and eventual neuronal cell loss. Current treatment options for AD provide temporary
symptomatic relief in a subset of patients. These drugs include cholinesterase inhibitors that improve
cholinergic innervation such as rivastigmine, donepezil and galatamine. In addition, memantine, a Nmethyl-
D-aspartate antagonist, is used to treat moderate to severe AD by reducing excitotoxicity. It has
been proposed that increased excitation and decreased inhibition lead to aberrant excitatory neuronal
activity and cognitive deficits in AD.
Methods: We undertook a search of the literature using bibliographic databases to identify publications
that were related to neuronal activity in Alzheimer's disease. We further delineated the publications to
determine inclusion/exclusion criteria based on relevance to increased excitation or decreased inhibition
of neuronal networks in both human patients and rodent models. The final criteria related to the potential
use of α-Melanocyte stimulating hormone (α-MSH) as a potential treatment strategy for Alzheimer's
disease. These data were utilized to obtain the content of this review.
Results: We identified 156 peer-reviewed publications that met our criteria and describe the findings
here. Rodent models of AD and ageing both exhibit cognitive deficits and loss of inhibitory GABAerigc
interneurons. α-Melanocyte stimulating hormone is a neuropeptide that is down-regulated in the brain
and cerebrospinal fluid of AD patients. α-MSH has many functions in the central nervous system including
neuroprotective and anti-inflammatory effects that target multiple aspects of the AD pathology.
α-MSH treatment promoted the survival of GABAergic interneurons in the hippocampus and improved
spatial memory as well as alterations in anxiety in a mouse model of AD. The somatostatin expressing
subpopulation of GABAergic interneurons are particularly preserved by α-MSH treatment. Somatostatin
has been implicated in hippocampal-dependent cognitive tasks. Somatostatin-expressing interneurons
have also been shown to play an important role in maintaining excitatory-inhibitory balance. α-MSH
preserved GABAergic interneurons and by preventing the loss of the somatostatin subpopulation, it improved
Conclusion: α-MSH is a novel candidate for the treatment of AD but its therapeutic potential in AD
patients remains to be investigated.