Synaptic dysfunction, together with neuritic plaques, neurofibrillary tangles and cholinergic neuron loss is an established finding in the Alzheimer’s disease (AD) neocortex. The synaptopathology of AD is known to involve both pre- and postsynaptic components. However, the status of rabphilin 3A (RPH3A), which interacts with the SNARE complex and regulates synaptic vesicle exocytosis and Ca²⁺-triggered neurotransmitter release, is at present unclear. In this study, we measured RPH3A and its ligand rab3A as well as several SNARE proteins in postmortem neocortex of patients with AD, and found specific reductions of RPH3A immunoreactivity compared with aged controls. RPH3A loss correlated with dementia severity, cholinergic deafferentation, and increased β-amyloid (Aβ) concentrations. Furthermore, RPH3A expression is selectively downregulated in cultured neurons treated with Aβ peptides. Our data suggest that presynaptic SNARE dysfunction forms part of the synaptopathology of AD.

Reference

Tan MG, Lee C, Lee JH, Francis PT, Williams RJ, Ramírez MJ, Chen CP, Wong PT, Lai MK (This paper).

Dementia with Lewy bodies and Parkinson’s disease dementia are different clinical phenotypes of Lewy body dementias (LBD) differentiated by the temporal relationship between parkinsonism and dementia onset. At present, it is unclear whether the glutamatergic system is affected in these disorders. In this study, we measured α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA subunits in the postmortem neocortex of a cohort of prospectively studied Lewy body dementia cases, as well as age-matched controls by immunoblotting. We found moderate losses of GluA2/3/4 immunoreactivities in LBD which correlated with higher predeath Hoehn & Yahr scores, a measure of motor disabilities; but not with dementia severity, cortical Lewy body burden, or amyloid plaque and neurofibrillary tangle burden. Our study suggests that GluA2/3/4 losses may be a neurochemical marker of motor disability in Lewy body dementias. Given recent proposals to use AMPA receptor antagonists in Parkinson’s disease, especially for levodopa-induced dyskinesia (Johnson et al. 2009), our data suggest both potential and caution in extending such therapeutic rationales to LBD in view of altered levels of receptor drug targets.

References

Mohamed NE, Howlett DR, Ma L, Francis PT, Aarsland D, Ballard CG, McKeith IG, Chen CP, Lai MK (This paper).

Johnson KA, Conn PJ, Niswender CM (2009) Glutamate receptors as therapeutic targets for Parkinson’s disease. CNS Neurol Disord Drug Targets 8:475-491.