Investigating synaptic dysfunction in people with Down's syndrome and Alzheimer's disease

Abstract

Down’s syndrome (DS), also known as trisomy 21, is the most common genetic disorder that results in learning disabilities (LD). The incidence of DS is around 1 in 800 live births; it is caused by the inheritance of an extra copy of all or part of chromosome 21 (Hsa21). People with DS have a high risk of developing neurofibrillary tangles and senile plaques characteristics of Alzheimer’s disease (AD) at an earlier age, around the age of 40, than the typical population. Synaptic dysfunction and neuronal loss are also key features of AD that are closely linked to cognitive and behavioural changes. There is limited evidence regarding whether aberrations in synapse trigger additional AD pathology. The DS population has fewer neurons from early age in comparison to the typically developing population. Interestingly, reduced levels of synaptic proteins have been associated with cognitive decline in AD. Also, there is growing evidence of an association between the endocytosis process and the pathological mechanism of AD. Enlarged early endosomes is a feature of AD that has been observed in DS prior to the onset of AD pathology. Out of 233 coding genes on Hsa21 there are two genes coding synaptic proteins, synaptojanin-1 (SYNJ1) and intersectin-1 (ITSN-1), involved in the endocytosis process. However, their role in DS subjects with AD have not been clearly defined to date. Investigations into such proteins may give an insight into pathological pathways that underly AD, not only in DS but also in the general population. I therefore hypothesised that the extra copy of the synaptic proteins SYNJ1 and ITSN-1 on Hsa21 in DS may be associated with synaptic changes and consequently with the pathological and clinical features of DS. In order to test this hypothesis a collection of available DS cases was obtained from various brain banks, together with control cases matched for age to the DS cases and AD cases matched to Braak stage of the DS cases. In addition to the standard neuropathological information, biochemical measurements were established for amyloid β (Aβ1-42), total tau (tTau) and tau phosphorylated at threonine181 (pTau181) in DS cases, Braak-matched AD cases and control, in the frontal and temporal cortices. This quantitative data was assessed in relation to Has-21 synaptic proteins and non-Hsa21 synaptic proteins, synaptophysin (SYP) and postsynaptic density protein-95 (PSD95). In general, there was a lack of comprehensive clinical data available for the DS cases, however relationships to cognitive status was investigated in a 2 sub-set of DS cases. Findings of this thesis suggested a strong association between the short isoform of ITSN-1 (ITSN-1-S) and AD pathology. While other synaptic proteins of interest demonstrated variabilities in relation to AD biochemical scores, the levels of ITSN-1-S predicted the density of soluble Aβ1-42 and pTau181/tTau in both regions and the density of insoluble Aβ1-42 and pTau181/tTau in the frontal cortex. The levels of ITSN-1-S predicted the age at dementia onset of DS. People with DS and dementia demonstrated a great loss in the levels of SYP, ITSN-1-L and PSD95 in the frontal cortex. The levels of SYNJ1 were significantly higher than subjects with early-stage dementia. Consistent with recent neuroimaging studies, the distribution of AD pathology in the frontal cortex DS might precede the temporal cortex. Very recently a novel mouse model of DS, Dp1Tyb mouse became available. A very small number of mice were available, preliminary findings indicated that there may be some changes in synaptic proteins may be present from an early age. These results need confirming and extending investigations. Overall this thesis provides new insights into the relationship between Hsa21 and non-Hsa21 synaptic proteins and clinical and pathological features of AD in DS that may form the basis of a better und