Year: 2012
Type: article
Abstract: Brain lipid metabolism has been increasingly appreciated as playing a central role in late-onset Alzheimer's disease (LOAD) etiology. Distinct alterations in brain membrane phospholipid composition, metabolism and selected lipid-processing enzymes are found postmortem in advanced AD brains. These changes correlate with neuropathological findings of senile plaques and neurofibrillary tangles, and with clinical measures of cognitive decline. Certain changes in phospholipid composition are exaggerated by an ApoE-e4 genotype, one major risk factor of LOAD. It is also known that ApoE secretion by astrocytes is modulated by phospholipid transfer protein (PLTP), and cerebrospinal fluid (CSF) ApoE levels correlate with CSF PLTP activity. Recent studies have also linked specific phospholipid-associated endocytic proteins to biology of AD. For example, studies have shown that genetic perturbation of synaptojanin 1 (synj1), a phosphoinositol (4,5) biphosphate (PI (4,5) P2) phosphatase which controls PI (4,5) P2 levels, can rescue Ab-induced neurotoxic effects such as long-term potentiation (LTP) suppression and behavioral deficits in a Down's syndrome transgenic mouse model. Furthermore, the same groups showed that oligomer Aβ reduces PIP2 which may account for oligomer Aβ induced synaptic dysfunction. We have undertaken the studies of possible roles for synaptojanin 1 in regulating metabolism of amyloid precursor protein (APP) and Aβ homeostasis, to test the hypothesis that aberrant phospholipid alterations may contribute to AD pathogenesis. Utilizing siRNA technique to down-regulate synj1 expression levels in cells, we analyzed the amounts of amyloid secreted into media, as well as other c-terminal fragments (β/αCTF) of APP. Furthermore, amyloid load in AD transgenic animals carrying synj1 haploinsufficiency was compared to that of synj1 wildtype animals. We then studied the amount of ApoE secreted in primary neurons/astrocytes derived from synj1 knockout animals. Our data suggests that genetic knockdown of synaptojanin 1 (synj1) decreases Ab levels in cell culture, and reduces amyloid load in AD transgenic animals. The amounts of β CTF are increased. Further, there is a significantly increase of ApoE secretion in cortical neuron/astrocyte culture derived from synj1 -/- animals if compared to controls. Together, our results suggest that one phosphoinositol modulator, synaptojanin 1, can regulate amyloid homeostasis, likely through its effects on Aβ generation and clearance.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1981707488