mucke lab

Aβ Toxicity
Because we focus on diseases that are clinically characterized by cognitive impairments, we increasingly complement our molecular and neuropathological studies with evaluations of CNS function. In a collaboration with Drs. Roger Nicoll and Robert Malenka at UCSF we examined what effects neuronal expression of AD-mutant hAPP and Aβ has upon neuronal communication in the hippocampus. Neural circuits in the hippocampus play a key role in the formation of memories and are severely disrupted in AD. Electrophysiological recordings of neuronal responses in hippocampal slice preparations from hAPP transgenic mice and nontransgenic littermate controls revealed major synaptic transmission deficits in the transgenic mice. Similar to cognitive impairments in AD, the synaptic transmission deficits increased with age. Notably, these functional neuronal impairments were seen well before the formation of amyloid plaques and, like the loss of immunolabeled presynaptic terminals, correlated with Aβ levels, but not with hAPP or plaque load. Decreasing hAPP expression levels while increasing Aβ production further augmented the synaptic transmission deficits, consistent with an insidious role of the Aβ peptide in the disease process. A correlation between cognitive decline in patients with AD and accumulation of Aβ in brain plaques has been reported by some researchers, but many others have failed to find such a relationship. Our studies suggest that high levels of Aβ can be neurotoxic independent of plaque formation. These results provide a circuit-level explanation for the discrepancies observed between plaque load and functional deficits in people with AD. Our findings have important implications for the design of new treatments for AD: inhibiting plaque formation may not be enough to prevent Aβ toxicity in the brain; to achieve this therapeutic goal, it may be necessary to inhibit the intracellular accumulation of Aβ or to block the activity of diffusible Aβ species.

ApoE
Inheritance of the APOE e4 allele is the most reproducible genetic risk factor for the most frequent form of AD; it also appears to worsen outcome after cerebral ischemia or head injury. Characterizing the effects of the most frequent human apoE isoforms (E3 and E4) on brain cells should provide insights into central apoE functions and help elucidate how the E4 variant promotes neurodegeneration and impairs cognition in aging. Together with Drs. Robert Mahley, Robert Pitas, and Jacob Raber, we compared the CNS effects of human apoE isoforms by expressing apoE3 or apoE4 at comparable levels in the brains of murine apoE-deficient (Apoe^–/–) mice. ApoE3 effectively prevented or delayed age-related and excitotoxin-induced neurodegeneration, as well as Aβ-induced cognitive deficits, whereas apoE4 did not. Moreover, apoE4 interfered with neuroprotective apoE3 functions and induced age-dependent memory deficits in female mice. Taken together, these findings help explain why Alzheimer’s disease develops more often and at an earlier age in people with apoE4 than in people with apoE3. They also suggest that blocking dominant negative effects of apoE4 will be critical in the development of apoE-targeted drug treatments. Ongoing studies address the mechanisms underlying the isoform-specific effects of apoE on Aβ-induced cognitive deficits.