According to the overflowing bathtub analogy, either a blocked drain (not enough clearance), an oversized faucet (too much production), or a combination, contributes to the accumulation of amyloid-β (Aβ) peptides in the Alzheimer disease (AD) brain. The solution to the problem, therefore, would be to unplug the drain or turn off the faucet. In this week’s Journal of Neuroscience, Jie Shen, Brigham and Women’s Hospital, Boston, and colleagues report that shutting off the spigot does help relieve symptoms in a mouse model of AD. Unfortunately, the relief seems only temporary.
The spigot in this case is γ-secretase, one of two enzymes necessary to clip Aβ from the larger Aβ precursor protein (APP). In 2001 (see ARF related news story), Shen and colleagues developed mice in which one of the essential components of γ-secretase, presenilin 1 (PS1), was conditionally “knocked out” (cKO). Because PS1 is essential for embryonic development and for the health and maintenance of adult non-neuronal tissues, Huakui Yu and colleagues designed these cKOs so that PS1 is ablated only postnatally and only in the pyramidal neurons of the cortex. Now, first author Carlos Saura at Shen’s lab, with help from colleagues at Gunnar Gouras’s lab at Cornell University, New York, and Richard Morris’s lab in Edinburgh, Scotland, has taken advantage of these mice to test how loss of PS1 helps mice suffering from AD-like pathology—he crossed the cKO PS1 mice with PDAPP transgenic mice that express human AβPP harboring the Swedish and Indiana mutations that cause familial AD (see Mucke et al., 2000.
When Saura and colleagues examined the PS1 cKO/PDAPP mice, they found that the levels of APP C-terminal fragments (CTFs) were dramatically higher than in the APP mice. This, plus failure to detect PS1 with anti-PS1 antibodies, confirmed the loss of the γ-secretase component, which helps to clear CTFs formed by the action of α- and β-secretases. The authors also found that the increase in CTFs, detected in mice as young as 2 months old, was age-dependent, getting worse as the animals got older, and that the fragments accumulated mostly in the presynaptic terminals.
In contrast, Saura and colleagues found that the age-dependent accumulation of Aβ normally seen in PDAPP animals was absent in mice that were also missing PS1. At 2, 6, and 17 months, Aβ42 was about 55, 90, and 99 percent lower in the PS1 cKO/PDAPP than in the PDAPP controls. When the authors tested for Aβ40, they found similar reductions.
These experiments confirmed that the spigot was indeed turned off—or at least down since the second presenilin, PS2, was presumably still active—and that the bathtub was no longer overflowing. But were the mice squeaky clean?
Cognitively, the mice lacking PS1 performed better than the control animals, suggesting that some of the neuronal deficits that retard PDAPP animals were absent. However, the improvement was only seen in very young mice. For example, when Saura and colleagues tested 3-month-old animals in a fear conditioning test, they found that the PDAPP animals performed significantly poorer than PS1 cKO/PDAPP or control wild-type mice. But by 6 months old, the PS1-negative mice, despite little accumulation of Aβ, were, in fact, performing worse than the PDAPP mice. A similar age-dependent rescue was found when the authors tested spatial memory using a water maze. At 3 months, the PS1 cKO/PDAPP mice performed as well as control wild-type animals, whereas the PDAPP mice were significantly weaker, but by 15-17 months, both PS1-negative and -positive PDAPP mice were performing the same and significantly poorer than wild-type animals.
To better understand the reasons for the memory impairments, the authors turned to electrophysiological measurements. When they measured neurotransmission in hippocampal slices isolated from the mice, they found that basal transmission, while normal at three months, was reduced by about 20 percent in both sets of transgenic animals by 6 months old. Also, long-term potentiation (LTP), or the ability of neurons to up the ante in response to repetitive stimuli and fire off stronger signals of their own, was compromised. In 6-month-old mice, LTP, which is required for learning and memory, was significantly reduced in PDAPP animals, which is to be expected given previous reports showing that Aβ can depress LTP (see ARF related news story). But Saura and colleagues also found that LTP was depressed to a similar degree in 6-month-old PS1 cKO/PDAPP mice, which do not accumulate the peptide.
Why the improvement in learning and memory deficits is not maintained throughout the lives of the PS1-negative transgenic mice is not clear, but the authors do suggest that “any beneficial effect on learning that results may be more than offset by other biochemical changes taking place in these older mice.” One obvious change in these animals is the accumulation of the AβPP C-terminal fragments at synapses. The failure to clear these fragments might turn out to be as bad for neurons as generation of Aβ.
So where does this leave γ-secretase inhibition as a therapeutic approach to treating AD? The data suggest that closing the spigot by inhibiting PS1 could, at the very least, provide temporary relief. Of course, in human AD cases, AβPP is not being overproduced as it is in the PDAPP animals, so the potential complication of a flood of CTFs might be less of an issue.—Tom Fagan
- Mouse Presenilin-1 Knockouts Have Lowered Levels of Aβ Peptides
- Earliest Amyloid Aggregates Fingered As Culprits, Disrupt Synapse Function in Rats
- Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000 Jun 1;20(11):4050-8. PubMed.
No Available Further Reading
- Saura CA, Chen G, Malkani S, Choi SY, Takahashi RH, Zhang D, Gouras GK, Kirkwood A, Morris RG, Shen J. Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci. 2005 Jul 20;25(29):6755-64. PubMed.