Synucleinopathies: not all early memory deficits lead to dementia

Parkinson’s disease (PD) is mainly known for the motor symptoms, which are caused by the death of neurons in the mesencephalon. However, this disease is also often associated with with Lewy bodies dementia (LBD), which is a chronic cognitive deterioration carrying hallucinations and other non-motor symptoms, characterized by cellular inclusions called Lewy bodies. Dementia is preceded by early manifesting memory deficits that, in PD and LBD, have been associated with the accumulation of misfolded α-synuclein proteins in the hippocampus and the cortex.

 Not all early memory deficits, however, develop into dementia. Sometimes, they disappear; other times they worsen, but remain restricted to the memory domain; other times they finally degenerate into dementia, that is a loss of function in all behavioral domains. Investigating the mechanisms that regulate these processes is critical for understanding the nature and fate of early cognitive symptoms, for their prognostic value in the onset of dementia, and for an early intervention with restorative therapeutic strategies.

 The brain site of origin of proteinopathy affects disease onset and progression

In this study, we have tested the hypothesis that the progression from early memory impairment to dementia may depend on the brain site of origin of α-synucleinopathy. In the brain, the hippocampus is important for the formation of long-term memory, while the mesencephalon regulates the motor and motivational functions through the release of the neurotransmitter dopamine.

We used a mouse model of site-specific overexpression of wild-type monomeric α-synuclein, which is supposed to be at the basis of cognitive symptoms (Giordan et al Brain 2018). We observed that when α-synucleinopathy originates in the hippocampus it causes early onset of specific memory and synaptic defects, and that these defects are due to an altered expression of glutamate receptors; yet, these cognitive symptoms remain stable for months and are not associated with neurodegeneration.

In contrast, when α-synucleinopathy originates in the midbrain it causes early sensorimotor deficits (Giordano et al Brain 2018) which are followed, months later, by a late onset of hippocampus-dependent memory deficits. The latter are associated with the loss of dopaminergic neurons and are concomitant with motor and non-motor symptoms, such as increased anxiety and endophenotypes of psychosis, which are similar to what is seen in LBD patients; thus, this behavioral impairment picture is comparable to human dementia, and is also associated with neurodegeneration.

 Brain connectomics may shape synucleinopathy patterns.

Our findings provide in vivo functional evidence in support of recent intriguing data¹ demonstrating that pathological α-synuclein initiated in different brain regions leads to distinct patterns of histopathological phenotypes in mice, depending on how much an area is linked with the others through direct/monosynaptic connections. The areas that are more connected may render the disease transmission easier, thus favoring the loss of not one, but more cerebral functions, as it happens in dementia (Figure 1). Additionally, the aggregational state of α-synuclein can further amplify this process: fibrillar α-synuclein, which can move trans-synaptically, goes beyond the monosynaptic connections and acquires the ability to influence wider brain networks, with an exponential impact on disrupting brain functions.

References

1. Rahayel, S. et al. Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns. Brain 145, 1743–1756 (2022).