Alzheimer’s disease (AD), the most common cause of dementia, is a major health problem in aging populations [
1]. AD is characterized by the extracellular accumulation of amyloid β (Aβ) and the intracellular accumulation of neurofibrillary tangles of hyperphosphorylated tau protein leading to neuronal death. Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are responsible for the familial early-onset AD, which is relatively rare [
2]. Although
lifestyle and environmental factors have emerged as modulators of the susceptibility to AD [
3], the causes of the most common sporadic late-onset AD are largely unknown, and no effective therapy is available. Thus, identification of novel risk factors and their mechanisms of action has important public health implications. Hyperhomocysteinemia (HHcy) is an emerging risk factor for AD [
4]. However, mechanism(s) underlying the involvement of HHcy in AD are not fully understood. Specifically, it is not clear whether elevated levels of homocysteine (Hcy) itself or its downstream metabolites, such as Hcy-thiolactone (HTL) and
N-homocysteinylated proteins, can be involved in AD.
Cystathionine β-synthase (CBS) deficiency, the most prevalent inborn error in the sulfur amino acid metabolism [
5,
6], is biochemically characterized by severe HHcy, i.e., severely elevated levels of Hcy and its metabolites, Hcy-thiolactone [
7] and
N-Hcy-protein [
8,
9]. CBS deficiency affects the central nervous system and causes severe learning and intellectual disability [
5], reduced IQ [
10], psychosis, obsessive-compulsive and behavior/personality disorders [
11]. Accelerated brain atrophy associated with HHcy has been reported in healthy elderly individuals [
12], alcoholic patients [
13], and in AD patients [
14] who also show upregulated brain mTOR signaling [
15]. These phenotypes are also seen in an animal model of human CBS deficiency, the
Cbs-/- mouse. Specifically, in the
Cbs-/- mouse model, severe HHcy is accompanied by neurological impairments and cognitive deficiency characterized by attenuated problem-solving abilities, learning, short- and long-term memory [
16,
17]. The expression of the histone demethylase Phf8 was reduced, H4K20me1, mTOR signaling, and App were increased in brains of
Cbs-/- mice compared to
Cbs+/- sibling controls. Autophagy-related proteins Becn1, Atg5, and Atg7 were downregulated while neurodegeneration-related neurofilament-L (Nfl) and glial fibrillary acidic protein (Gfap) were upregulated in
Cbs-/- brains. Treatments with Hcy-thiolactone,
N-Hcy-protein or Hcy, or
Cbs gene silencing by RNA interference significantly reduced Phf8 expression and increased total H4K20me1 as well as mTOR promoter-bound H4K20me1 in mouse neuroblastoma N2a and N2a-APPswe cells. This caused transcriptional mTOR upregulation, autophagy downregulation, and significantly elevated APP and Aβ levels. The
Phf8 gene silencing increased Aβ, but not APP, levels. These findings show that Phf8 regulates Aβ synthesis and suggest that neuropathy seen in mouse Cbs deficiency is mediated by Hcy metabolites, which transcriptionally dysregulate the Phf8->H4K20me1->mTOR->autophagy pathway thus increasing Aβ accumulation [
18]. Phospho-Tau level was also elevated in
Cbs-/- mouse brain [
19].
Because
N-homocysteinylated by Hcy-thiolactone is detrimental to protein’s function and biological integrity [
9,
20,
21,
22,
23], enzymes detoxifying Hcy-thiolactone have evolved: serum paraoxonase 1 (PON1) [
24], cytoplasmic bleomycin hydrolase (BLMH) [
25], and mitochondrial biphenyl hydrolase-like (BPHL) enzyme [
26,
27,
28], all of which hydrolyze Hcy-thiolactone to Hcy. The enzymatic detoxification reaction protects proteins from
N-homocysteinylation [
24,
29] because it eliminates Hcy-thiolactone, which would otherwise damage them [
9,
20,
22,
30,
31].
Accumulating evidence suggests that Hcy-thiolactone hydrolyzing enzymes PON1, BLMH, and BPHL play an important role in the central nervous system. This review provides an overview of current understanding of the biological function of Hcy-thiolactone-detoxifying enzymes and of the consequences of their impairment leading to phenotypes characteristic of AD. To provide a context for the discussion of Hcy-thiolactone-detoxifying enzymes, Hcy metabolism, biogenesis, and chemical biology of Hcy-thiolactone and N-homocysteinylated proteins are also briefly summarized.