PROJECT SUMMARY
Alzheimer’s disease (AD) is a devastating age-associated degenerative brain disease and the most common
cause of dementia. By age 85, more than 30% of individuals will have AD. To date, there are no preventive
measures or effective cures; hence novel treatment strategies are urgently needed.
AD is characterized by memory decline, cognitive dysfunction, amyloid-beta (Aß) deposition,
neurofibrillary tangles and neuroinflammation [1]. However, anti-inflammatory treatments have been largely
unsuccessful, prompting us to reassess the contribution of tissue-resident microglia to AD onset and progression.
While some reports show that pro-inflammatory microglia are associated with disease progression [2], recent
technological advances allowing single-cell analysis have identified protective disease-associated microglia
(DAM) and their distinct phenotypic characteristics [3].
A feature of these protective DAMs is lipoprotein Lipase (LPL), the rate-limiting enzyme in the hydrolysis
of triglyceride (TG)-rich lipoproteins. These findings add to a growing body of literature highlighting a protective
role of LPL in AD pathophysiology. For example, single-nucleotide polymorphisms (SNPs) in the coding region
of the LPL gene are associated with reduced enzyme activity and increased AD risk [4]. Recent studies suggest
that glial-LPL facilitates phagocytic uptake and degradation of Aß [5, 6], suggesting that LPL-mediated protection
is due to enhanced Aß clearance. In support, our lab has recently shown that LPL is a feature of reparative
phagocytic microglia and is involved in lipid and lipoprotein clearance [7]. Importantly, our preliminary data show
that the LPL activator, NO-1886, can elevate LPL abundance and activity in microglia. In addition, while
microglial-LPL can facilitate uptake of ApoE (Isoforms 2 and 3) containing lipoproteins, both the hydrolytic and
endocytotic function of LPL is inhibited by ApoE4. Taken together these findings have led to our central
hypothesis, that enhancing microglial LPL abundance will facilitate endocytosis and clearance of Aß and ApoE
containing HDL-like lipoproteins in the CNS to ameliorate the progression of AD. To test this hypothesis, in AIM
I. we will determine the feasibility of NO-1886 to modulate biochemical and behavioral features of AD in an
established mouse model of AD (5XFAD); and in AIM II we will adopt a multisystem approach to determine the
mechanism of microglial LPL-mediated Aß and ApoE (2, 3 and 4) uptake.
This R21 application brings together an interdisciplinary research team with vast expertise in lipid and
lipoprotein biochemistry (Drs. Eckel and Bruce), and the cellular basis of AD pathogenesis (Dr. Potter) that are
uniquely positioned to determine the role of LPL in AD, and to test the feasibility of the microglial LPL as a novel
target for AD treatment. Findings from these studies will serve to develop an exciting new program of research
that will quickly translate to treatments that will prevent, delay and/or reverse AD progression.