eNews July 27, 2011

Caveolin 1 deficiency plays a role in age-related neurodegeneration

How healthy are your brain's synapses – those inter-neuronal junctions that allow electrical and chemical signals to be transmitted from one neuron to another? Evidence indicates that they degrade with age and make us more susceptible to neurodegenerative diseases, such as Alzheimer's and Parkinson's. Understanding why this happens could help scientists develop therapies to prevent, stop or even reverse synapse decay. A research team led by Drs. Brian Head and Hemal Patel at the University of California San Diego (UCSD), La Jolla, California, and VA San Diego, has shown that, in mice, one of the reasons for age-related synapse degradation is the age-related decline in the expression of the cholesterol-binding protein caveolin 1 (Cav1) (Head et al. 2010).

Membrane/lipid rafts, cholesterol and caveolin 1

To develop, stabilize and function properly, synapses depend on neuronal plasma membrane units called membrane/lipid rafts (MLRs). One of the major components of MLRs is cholesterol, which, along with other lipids, is essential for effective neurotransmission. In MLRs, cholesterol binds to Cav1, which organizes synaptic components of the neurotransmitter and neurotrophic receptor signaling pathways. MLRs and cholesterol are known to mitigate the damage caused by the amyloid-beta (AB) toxicity in Alzheimer's disease, and age-related defects in the biosynthesis, transport or uptake of cholesterol are thought to mediate neurodegeneration.

Age-related caveolin 1 loss is tied to age-related synapse loss

The UCSD team wanted to know if age-related synapse loss is due to age-related caveolin 1 loss. To determine this, they compared the levels of Cav1 and synaptic signaling molecules in MLRs, the number of synapses, and the degree of neurodegeneration in the brains of young, middle age and old C57BL/6J (B6J, 000664) controls and Cav1-deficient B6.Cg-Cav1tm1Mls/J mice (007083), which develop Alzheimer's-like pathologies. They found the following:

  • The amount of synaptic signaling molecules and caveolin 1 in the hippocampal MLRs and synaptosomes of B6J mice, decreases with age.
  • This decrease is more severe in Cav1-deficient mice.
  • The brains of old Cav1-deficient mice have significantly fewer synapses than either young Cav1-deficient mice or B6J controls.
  • Young Cav1-deficient mice show signs of premature neuronal aging and degeneration.
  • Young Cav1-deficient mice are more susceptible to cerebral ischemia-reperfusion injury than are young B6J mice.
  • Young Cav1-deficient mice have higher levels of AB, P-Tau and astrogliosis, and a lower cerebrovascular volume than young B6J controls.
  • Neuron-targeted re-expression of caveolin 1 in Cav1-deficient neurons in vitro decreases AB expression.

These results demonstrated that the loss of caveolin 1 accelerates neurodegeneration and aging in mice.

This is the first study to demonstrate that, in mice, the cholesterol-binding caveolin 1 protein in MLRs and the synaptic signaling molecules in the hippocampus form complexes that facilitate neurite outgrowth and axonal branching and guidance, form and stabilize synapses, protect neurons against ischemic injury, and possibly mitigate the AB toxicity associated with Alzheimer's. They show that these Cav1/MLR complexes are disrupted with age. They also demonstrate that Cav1-deficient mice develop an Alzheimer’s-like neuropathology (AB production, elevated astrogliosis, hippocampal neuronal loss and reduced cerebrovasculature), making them an Alzheimer's mouse model that doesn't harbor any of the three commonly known Alzheimer’s-associated gene mutations – amyloid precursor protein (App), presenilin 1 (Psen1) and presenilin 2 (Psen2). The findings by Head and Patel may help researchers develop therapies for preserving neuronal function or repair neuronal damage due to injury or neurodegenerative diseases such as Alzheimer's.